Modified forms of pharmacologically active agents and uses therefor

ABSTRACT

In accordance with the present invention, there are provided modified forms of nonsteroidal anti-inflammatory drugs (NSAIDs). Modified NSAIDs according to the invention provide a new class of anti-inflammatory agent which provide the therapeutic benefits of NSAIDs while causing a much lower incidence of side-effects then typically observed with such agents.

This application is a continuation-in-part of U.S. Ser. No. 09/602,688,filed Jun. 23, 2000.

FIELD OF THE INVENTION

The present invention relates to novel forms of pharmacologically activeagents, and methods for the preparation and use thereof. In a particularaspect of the invention, methods are provided for treating pathologicalconditions with a modified form of one or more pharmacologically activeagents, thereby reducing the occurrence of side-effects caused thereby.

BACKGROUND OF THE INVENTION

Despite the advent of modem pharmaceutical technology, many drugs stillpossess untoward toxicities which often limit the therapeutic potentialthereof. For example, although nonsteroid antiinflammatory drugs(NSAIDs) are a class of compounds which are widely used for thetreatment of inflammation, pain and fever, NSAIDs (e.g., naproxen,aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, aside effect that remains the major limitation to the use of NSAIDs (see,for example, J. L. Wallace, in Gastroenterol. 112:10001016 (1997); A. H.Soll et al., in Ann Intern Med. 114:307319 (1991); and J. Bjarnason etal., in Gastroenterol. 104:18321847 (1993)).

There are two major ulcerogenic effects of NSAIDs: (1) irritant effectson the epithelium of the gastrointestinal tract and (2) suppression ofgastrointestinal prostaglandin synthesis. In recent years, numerousstrategies have been attempted to design and develop new NSAIDs thatreduce the damage to the gastrointestinal tract. These efforts, however,have largely been unsuccessful. For example, enteric coating or slowrelease formulations designed to reduce the topical irritant propertiesof NSAIDs have been shown to be ineffective in terms of reducing theincidence of clinically significant side effects, including perforationand bleeding (see, for example, D. Y. Graham et al., in Clin. Pharmacol.Ther. 38:6570 (1985); and J. L. Carson, et al., in Arch. Intern. Med.,147:10541059 (1987)).

It is well recognized that aspirin and other NSAIDs exert theirpharmacological effects through the non-selective inhibition ofcyclooxygenase (COX) enzymes, thereby blocking prostaglandin synthesis(see, for example, J. R. Van in Nature, 231:232235 (1971)). There aretwo types of COX enzymes, namely COX1 and COX2. COX1 is expressedconstitutively in many tissues, including the stomach, kidney, andplatelets, whereas COX2 is expressed only at the site of inflammation(see, for example, S. Kargan et al. in Gastroenterol., 111:445454(1996)). The prostagladins derived from COX1 are responsible for many ofthe physiological effects, including maintenance of gastric mucosalintegrity.

Many attempts have been made to develop NSAIDs that only inhibit COX2,without impacting the activity of COX1 (see, for example, J. A. Mitchellet al., in Proc. Natl. Acad. Sci. USA 90:1169311697 (1993); and E. A.Meade et al., in J. Biol. Chem., 268:66106614 (1993)). There are severalNSAIDs presently on the market (e.g., rofecoxib and celecoxib) that showmarked selectivity for COX2 (see, for example, E. A. Meade, supra.; K.Glaser et al., in Eur. J. Pharmacol. 281:107111 (1995) andKaplan-Machlis, B., and Klostermeyer, B S in Ann Pharmacother.33:979-88, (1999)). These drugs appear to have reduced gastrointestinaltoxicity relative to other NSAIDs on the market.

On the basis of encouraging clinical as well as experimental data, thedevelopment of highly selective COX2 inhibitors appears to be a soundstrategy to develop a new generation of antiinflammatory drugs. However,the physiological functions of COX1 and COX2 are not always welldefined. Thus, there is a possibility that prostagladins produced as aresult of COX1 expression may also contribute to inflammation, pain andfever. On the other hand, prostagladins produced by COX2 have been shownto play important physiological functions, including the initiation andmaintenance of labor and in the regulation of bone resorption (see, forexample, D. M. Slater et al., in Am. J. Obstet. Gynecol., 172:7782(1995); and Y. Onoe et al., in J. Immunol. 156:758764 (1996)), thusinhibition of this pathway may not always be beneficial. Consideringthese points, highly selective COX2 inhibitors may produce additionalside effects above and beyond those observed with standard NSAIDs,therefore such inhibitors may not be highly desirable.

Accordingly, there is still a need in the art for modified forms ofNSAIDs which cause a reduced incidence of side-effects, relative to theincidence of side-effects caused by such pharmacologically active agentsin unmodified form.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a new classof modified NSAIDs which cause a much lower incidence of side-effectsthan are typically observed with unmodified NSAIDs due to the protectiveeffects imparted by modifying the NSAIDs as described herein.

There are a number of advantages provided by modified NSAIDs accordingto the invention including one or more of the following:

(i) reduced irritant effects (e.g., contact irritation) of NSAIDs,

(ii) enhanced tissue delivery of the drug as a result of a decrease innet charges on the molecule, particularly for acidic NSAIDs such asnaproxen, aspirin, diclofenac and ibuprofen, thereby reducing thequantity of material which must be delivered to achieve an effectivedosage, and

(iii) reduction in the maximum concentration (Cmax,) achieved uponadministration to a subject relative to the unmodified NSAID, whilemaintaining a therapeutically effective concentration of the NSAID inplasma of the subject.

In accordance with the present invention, cleavage of the modifiedNSAIDs described herein from the modified group appended theretoreleases the pharmaceutically active agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the total length of intestinal ulcers measured afterthree daily doses of NSAID in unfasted male Sprague-Dawley rats (150-200g) treated with vehicle, naproxen, or equimolar invention composition(compound 19). *P<0.05 by unpaired t-test.

FIG. 2 illustrates the total length of intestinal ulcers measured after14 daily doses of NSAID in unfasted male Sprague-Dawley rats (150-200 g)treated with vehicle (bar 7), three doses of naproxen (bar 1:50 mg/kg,bar 2:45 mg/kg, bar 3:40 mg/kg), or three equimolar doses of inventioncomposition (compound 19) (bars 4-6). *P<0.05 by unpaired t-test vs.corresponding dose of naproxen.

FIG. 3 illustrates the inhibition of paw volume increases in theuninjected feet of Lewis male rats in which arthritis was induced byintradermal injection of adjuvant into the footpad. Rats were injectedon day 0 and treated once daily from days 8 to 15 with vehicle, naproxen(10 mg/kg), or invention composition (compound 19) at equivalent dose.Paw volumes were measured with a Plethysmometer on days 5 and 15. Closedcircles=naproxen; squares=invention composition.

FIG. 4 compares naproxen plasma concentration-time profiles (n=4,mean±s.d.) after oral administration of naproxen (darkened circles) at 2mg/kg and modified naproxen (open triangles) at an equivalent dose of 2mg/kg with respect to naproxen in rats. At predetermined times, bloodsamples were collected and centrifuged to obtain the plasma samples. Theplasma naproxen levels were measured by HPLC with a UV detection system.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided compoundscomprising a modified NSAID, wherein the NSAID is covalently attachedeither directly or through a linker molecule to a sulfur-containingfunctional group containing an optionally substituted hydrocarbylmoiety. Exemplary invention compounds have the structure:

X-L-Z

wherein:

X=a non-steroidal anti-inflammatory drug (NSAID),

L=an optional linker/spacer, and

Z=a sulfur-containing functional group containing an optionallysubstituted hydrocarbyl moiety.

NSAIDs contemplated for modification in accordance with the presentinvention include acetaminophen (Tylenol, Datril, etc.), aspirin,ibuprofen (Motrin, Advil, Rufen, others), choline magnesium salicylate(Triasate), choline salicylate (Anthropan), diclofenac (voltaren,cataflam), diflunisal (dolobid), etodolac (lodine), fenoprofen calcium(nalfon), flurbiprofen (ansaid), indomethacin (indocin, indometh,others), ketoprofen (orudis, oruvail), carprofen, indoprofen, ketorolactromethamine (toradol), magnesium salicylate (Doan's, magan, mobidin,others), meclofenamate sodium (meclomen), mefenamic acid (relafan),oxaprozin (daypro), piroxicam (feldene), sodium salicylate, sulindac(clinoril), tolmetin (tolectin), meloxicam, nabumetone, naproxen,lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenicacid, flosulide, and the like. Presently preferred NSAIDs employed inthe practice of the invention include naproxen, aspirin, ibuprofen,flurbiprofen, indomethacin, ketoprofen, carprofen, and the like. Whenthe NSAID is aspirin, the sulfur-containing functional groups—CH₂S(O)₂CH₃, —CH₂S(O)CH₃, and —SCH₃ are not presently preferred.

Invention compounds can be readily prepared in a variety of ways eitherby direct reaction of NSAIDs with the sulfur-containing functional groupor indirectly through a suitable linker molecule.

The components of invention compositions are directly or indirectlycovalently attached employing a variety of linkages (including anoptional linker), e.g., ester linkages, disulfide linkages, amidelinkages, immine linkages, enamine linkages, ether linkages, thioetherlinkages, imide linkages, sulfate ester linkages, sulfonate esterlinkages, sulfone linkages, sulfonamide linkages, phosphate esterlinkages, carbonate linkages, O-glycosidic linkages, S-glycosidiclinkages, and the like. Such linkages can be accomplished using standardsynthetic techniques as are well known by those of skill in the art,either by direct reaction of the starting materials, or by incorporatinga suitable functional group on the starting material, followed bycoupling of the reactants.

When the pharmacologically active agents contemplated for use hereincontain suitable functionality thereon, e.g., hydroxy, amino, carboxy,and the like, invention modified NSAIDs can be prepared by directlinkage between the two agents. Alternatively, the NSAIDs can befunctionalized so as to facilitate linkage between the two agents. Whenpresent, linker/spacer L has the following structure:

—W—R—

wherein:

R is optional, and when present is alkylene, substituted alkylene,cycloalkylene, substituted cycloalkylene, heterocyclic, substitutedheterocyclic, oxyalkylene, substituted oxyalkylene, alkenylene,substituted alkenylene, arylene, substituted arylene, alkarylene,substituted alkarylene, aralkylene or substituted aralkylene, and

W is ester, reverse ester, thioester, reverse thioester, amide, reverseamide, phosphate, phosphonate, imine, enamine, or the like.

Functional groups contemplated by the present invention aresulfur-based. Examples of suitable sulfur-containing functional groupsinclude sulfonate, reverse sulfonate, sulfonamide, reverse sulfonamide,sulfone, sulfinate, reverse sulfinate, and the like. In a particularaspect of the invention, the sulfur-based moiety is sulfonate or reversesulfonate. In a particularly preferred aspect of the invention, thesulfonate is an optionally substituted aromatic sulfonate such astosylate or brosylate.

Other preferred sulfur-based functional groups contemplated by thepresent invention include sulfones. Preferably, the sulfone is anoptionally substituted alkyl or aromatic sulfone.

In one aspect of the invention, Z may have the following structure:

—Y—S(O)n—Y′—Q

wherein:

each of Y and Y′ are optionally present, and when present areindependantly —O— or —NR′—, wherein R′ is H or an optionally substitutedhydrocarbyl moiety;

n is 1 or 2, and

Q is H or an optionally substituted hydrocarbyl moiety.

As employed herein, “hydrocarbyl” embraces alkyl, substituted alkyl,oxyalkyl, substituted oxyalkyl, cycloalkyl, substituted cycloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, monocyclicheterocyclic, substituted monocyclic heterocyclic, monocyclic aromatic,monosubstituted monocyclic aromatic, or the like.

As employed herein, “alkyl” refers to hydrocarbyl radicals having 1 upto 20 carbon atoms, preferably 2-10 carbon atoms; and “substitutedalkyl” comprises alkyl groups further bearing one or more substituentsselected from hydroxy, alkoxy (of a lower alkyl group), mercapto (of alower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic,substituted heterocyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, aryloxy, substituted aryloxy, halogen,trifluoromethyl, cyano, nitro, nitrone, amino, amido, C(O)H, acyl,oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and thelike.

As employed herein, “oxyalkyl” refers to the moiety —O-alkyl-, whereinalkyl is as defined above, and “substituted oxyalkyl” refers to oxyalkylgroups further bearing one or more substituents as set forth above.

As employed herein, “cycloalkyl” refers to cyclic ring-containing groupscontaining in the range of about 3 up to 8 carbon atoms, and“substituted cycloalkyl” refers to cycloalkyl groups further bearing oneor more substituents as set forth above.

As employed herein, “heterocyclic” refers to cyclic (i.e.,ring-containing) groups containing one or more heteroatoms (e.g., N, O,S, or the like) as part of the ring structure, and having in the rangeof 3 up to 14 carbon atoms and “substituted heterocyclic” refers toheterocyclic groups further bearing one or more substituents as setforth above.

As employed herein, “alkenyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon double bond, andhaving in the range of about 2 up to 12 carbon atoms, and “substitutedalkenyl” refers to alkenyl groups further bearing one or moresubstituents as set forth above.

As employed herein, “alkynyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon triple bond, andhaving in the range of about 2 up to 12 carbon atoms, and “substitutedalkynyl” refers to alkynylene groups further bearing one or moresubstituents as set forth above.

As employed herein, “monocyclic aromatic” refers to aromatic groupshaving in the range of 5 up to 7 carbon atoms and “monosubstitutedmonocyclic aromatic” refers to aromatic groups further bearing one ofthe substituents set forth above.

As employed herein, “alkylene” refers to divalent hydrocarbyl radicalshaving 1 up to 20 carbon atoms, preferably 2-10 carbon atoms; and“substituted alkylene” comprises alkylene groups further bearing one ormore substituents as set forth above.

As employed herein, “cycloalkylene” refers to cyclic ring-containinggroups containing in the range of about 3 up to 8 carbon atoms, and“substituted cycloalkylene” refers to cycloalkylene groups furtherbearing one or more substituents as set forth above.

As employed herein, “oxyalkylene” refers to the moiety —O-alkylene-,wherein alkylene is as defined above, and “substituted oxyalkylene”refers to oxyalkylene groups further bearing one or more substituents asset forth above.

As employed herein, “alkenylene” refers to divalent, straight orbranched chain hydrocarbyl groups having at least one carbon-carbondouble bond, and having in the range of about 2 up to 12 carbon atoms,and “substituted alkenylene” refers to alkenylene groups further bearingone or more substituents as set forth above.

As employed herein, “alkynylene” refers to divalent straight or branchedchain hydrocarbyl groups having at least one carbon-carbon triple bond,and having in the range of about 2 up to 12 carbon atoms, and“substituted alkynylene” refers to alkynylene groups further bearing oneor more substituents as set forth above.

As employed herein, “arylene” refers to divalent aromatic groups havingin the range of 6 up to 14 carbon atoms and “substituted arylene” refersto arylene groups further bearing one or more substituents as set forthabove.

As employed herein, “alkylarylene” refers to alkyl-substituted arylenegroups and “substituted alkylarylene” refers to alkylarylene groupsfurther bearing one or more substituents as set forth above.

As employed herein, “arylalkylene” refers to aryl-substituted alkylenegroups and “substituted arylalkylene” refers to arylalkylene groupsfurther bearing one or more substituents as set forth above.

As employed herein, “arylalkenylene” refers to aryl-substitutedalkenylene groups and “substituted arylalkenylene” refers toarylalkenylene groups further bearing one or more substituents as setforth above.

As employed herein, “arylalkynylene” refers to aryl-substitutedalkynylene groups and “substituted arylalkynylene” refers toarylalkynylene groups further bearing one or more substituents as setforth above.

Diseases and conditions contemplated for treatment in accordance withthe present invention include inflammatory and infectious diseases, suchas, for example, septic shock, hemorrhagic shock, anaphylactic shock,toxic shock syndrome, ischemia, cerebral ischemia, administration ofcytokines, overexpression of cytokines, ulcers, inflammatory boweldisease (e.g., ulcerative colitis or Crohn's disease), diabetes,arthritis (e.g., rheumatoid arthritis and osteoarthritis), asthma,Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis,allograft rejection, encephalomyelitis, meningitis, pancreatitis,peritonitis, vasculitis, lymphocytic choriomeningitis,glomerulonephritis, uveitis, ileitis, inflammation (e.g., liverinflammation, renal inflammation, and the like), burn, infection(including bacterial, viral, fungal and parasitic infections),hemodialysis, chronic fatigue syndrome, stroke, cancers (e.g., breast,melanoma, carcinoma, and the like), cardiopulmonary bypass,ischemic/reperfusion injury, gastritis, adult respiratory distresssyndrome, cachexia, myocarditis, autoimmune disorders, eczema,psoriasis, heart failure, heart disease, atherosclerosis, dermatitis,urticaria, systemic lupus erythematosus, AIDS, AIDS dementia, chronicneurodegenerative disease, pain (e.g., chronic pain and post-surgicalpain), priapism, cystic fibrosis, amyotrophic lateral sclerosis,schizophrenia, depression, premenstrual syndrome, anxiety, addiction,headache, migraine, Huntington's disease, epilepsy, neurodegenerativedisorders, gastrointestinal motility disorders, obesity, hyperphagia,solid tumors (e.g., neuroblastoma), malaria, hematologic cancers,myelofibrosis, lung injury, graftversushost disease, head injury, CNStrauma, hepatitis, renal failure, liver disease (e.g., chronic hepatitisC), drug-induced lung injury (e.g., paraquat), myasthenia gravis (MG),ophthalmic diseases, postangioplasty, restenosis, angina, coronaryartery disease, and the like.

In accordance with another embodiment of the present invention, thereare provided methods for the preparation of modified NSAIDs, said methodcomprising covalently attaching a NSAID to a sulfur-containingfunctional group containing an optionally substituted hydrocarbylmoiety. The resulting compound provides a latent form of thepharmacologically active agent, releasing the biological activitythereof only when the compound is cleaved (e.g., by an esterase, amidaseor other suitable enzyme).

As readily recognized by those of skill in the art, invention compoundscan be prepared in a variety of ways. See, for example, Schemes 1A and1B, wherein NSAID, X, bearing a carboxylic moiety can be reacted eitherdirectly with the sulfur-containing functional group (Scheme 1A) orindirectly through a linker molecule (Scheme 1B).

Employing these general reaction schemes, invention modified NSAIDs canbe prepared from a wide variety of pharmacologically active agents. See,for example, Examples 1-59 provided herein.

In accordance with yet another embodiment of the present invention,there are provided methods for reducing the side effects induced byadministration of NSAIDs to a subject, said method comprising reducingthe C_(max) relative to unmodified NSAIDs while maintaining atherapeutically effective concentration in plasma upon administration toa subject in need thereof. The reduction in C_(max) is achieved, forexample, by covalently attaching a sulfur-containing functional groupcontaining an optionally substituted hydrocarbyl moiety to said NSAIDprior to administration to said subject, as depicted in Schemes 1A and1B.

In a particular embodiment of the invention, the C_(max) is reducedrelative to the unmodified NSAID by about 10% to 90%. In a presentlypreferred embodiment, the C_(max) is reduced relative to the unmodifiedNSAID by about 20% to 80%. In a most preferred embodiment, the C_(max)is reduced relative to the unmodified NSAID by about 40% to 70%.

In accordance with still another embodiment of the present invention,there are provided methods for enhancing the effectiveness of NSAIDs,said method comprising reducing the C_(max) relative to unmodifiedNSAIDs while maintaining a therapeutically effective concentration inplasma upon administration to a subject in need thereof. The enhancedeffectiveness of said NSAIDs is achieved, for example, by covalentlyattaching a sulfur-containing functional group containing an optionallysubstituted hydrocarbyl moiety to said NSAID.

In accordance with a still further embodiment of the present invention,there are provided improved methods for the administration of NSAIDs toa subject for the treatment of a pathological condition, the improvementcomprising reducing the C_(max) relative to unmodified NSAIDs whilemaintaining a therapeutically effective concentration in plasma uponadministration to a subject in need thereof. The improvement isaccomplished, for example, by covalently attaching said NSAID to asulfur-containing functional group containing an optionally substitutedhydrocarbyl moiety prior to administration thereof to said subject.

Those of skill in the art recognize that the modified NSAIDs describedherein can be delivered in a variety of ways, such as, for example,orally, intravenously, subcutaneously, parenterally, rectally, byinhalation, and the like.

Depending on the mode of delivery employed, the modified NSAIDscontemplated for use herein can be delivered in a variety ofpharmaceutically acceptable forms. For example, the invention modifiedNSAIDs can be delivered in the form of a solid, solution, emulsion,dispersion, micelle, liposome, and the like.

Thus, in accordance with still another embodiment of the presentinvention, there are provided physiologically active composition(s)comprising invention modified NSAIDs in a suitable vehicle renderingsaid compounds amenable to oral delivery, transdermal delivery,intravenous delivery, intramuscular delivery, topical delivery, nasaldelivery, and the like.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a micelle, aliposome, and the like, wherein the resulting composition contains oneor more of the modified NSAIDs of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventionmodified NSAIDs may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers for tablets, pellets,capsules, suppositories, solutions, emulsions, suspensions, and anyother form suitable for use. The carriers which can be used includeglucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventionmodified NSAIDs are included in the pharmaceutical composition in anamount sufficient to produce the desired effect upon the process ordisease condition.

Pharmaceutical compositions containing invention modified NSAIDs may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of a sweetening agent such as sucrose, lactose, or saccharin,flavoring agents such as peppermint, oil of wintergreen or cherry,coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets containinginvention modified NSAIDs in admixture with non-toxic pharmaceuticallyacceptable excipients may also be manufactured by known methods. Theexcipients used may be, for example, (1) inert diluents such as calciumcarbonate, lactose, calcium phosphate or sodium phosphate; (2)granulating and disintegrating agents such as corn starch, potato starchor alginic acid; (3) binding agents such as gum tragacanth, corn starch,gelatin or acacia, and (4) lubricating agents such as magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,160,452; and 4,265,874, to form osmotic therapeutic tablets forcontrolled release.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention modified NSAIDs are mixed with aninert solid diluent, for example, calcium carbonate, calcium phosphateor kaolin. They may also be in the form of soft gelatin capsules whereinthe invention modified NSAIDs are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention modified NSAIDs contemplated for use in the practice of thepresent invention may also be administered in the form of suppositoriesfor rectal administration of the drug. These compositions may beprepared by mixing the invention modified NSAIDs with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquify and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

In general, the dosage of invention modified NSAIDs employed asdescribed herein falls in the range of about 0.01 mmoles/kg body weightof the subject/hour up to about 0.5 mmoles/kg/hr. Typical daily doses,in general, lie within the range of from about 10 μg up to about 100 mgper kg body weight, and, preferably within the range of from 50 μg to 10mg per kg body weight and can be administered up to four times daily.The daily IV dose lies within the range of from about 1 μg to about 100mg per kg body weight, and, preferably, within the range of from 10 μgto 10 mg per kg body weight.

In accordance with yet another embodiment of the present invention,there are provided improved methods for the treatment of a subjectsuffering from a pathological condition by administration thereto of aNSAID, the improvement comprising reducing the C_(max) relative tounmodified NSAIDs while maintaining a therapeutically effectiveconcentration in plasma upon administration to a subject in needthereof. The improvement is achieved, for example, by covalentlyattaching said NSAID to a sulfur-containing functional group containingan optionally substituted hydrocarbyl moiety prior to administrationthereof to said subject.

Thus, invention method for the treatment of a subject afflicted with apathological condition comprises administering to a subject an effectiveamount of a modified pharmacologically active agent,

wherein said pharmacologically active agent is a NSAID, and is effectivefor treatment of said condition, and

wherein said pharmacologically active agent has been modified to reducethe C_(max) relative to unmodified NSAIDs while maintaining atherapeutically effective concentration in plasma upon administration toa subject in need thereof. The modification is accomplished, forexample, by the covalent attachment to the NSAID of a sulfur-containingfunctional group containing an optionally substituted hydrocarbylmoiety.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

The syntheses described in Examples 1-8 are outlined in Scheme 2.

EXAMPLE 1

Compound 10 (Scheme 2). A mixture of Naproxen (1) (23 g, 0.1 mol),ethylene glycol (2) (27.9 ml, 0.5 mol) and toluenesulfonic acid (TsOH)(1.27 g, 6.7 mmol) in CHCl₃ was heated to reflux for 4 h. The reactionsolution was washed with water, 10% Na₂CO₃ solution and water. Theorganic layer was dried (Na₂SO₄) and the solvent was evaporated. Theresidue was purified by crystallization from CH₂Cl₂ and hexanes to give25.7g (94%) of the compound 10 as a white crystal; ¹H NMR (CDCl₃) δ1.59(d, 3H), 1.62 (br, 1H, ex D₂O), 3.74 (t, 2H), 3.90 (q, 1H), 3.91 (s,3H), 4.21 (t, 2H), 7.39 (d, 1H), 7.69 (m, 3H); ¹³C NMR (CDCl₃) δ18.7,45.6, 55.5, 61.4, 66.6, 105.8, 119.3, 126.1, 126.2, 127.5, 129.1, 129.5,133.9, 135.7, 157.9, 175.2; MS (ESI) m/z 273 (M−1).

Compound 18 (Scheme 2). To a solution of compound 10 (24.5 g, 89 mmol)in 100 ml of pyridine was added tosyl chloride (TsCl) (34.1 g, 179mmol). The resulting solution was stirred at 0° C. for 2.5 h. Thereaction solution was then poured into 300 ml of water and then 200 mlof ether was added. The layers were separated and the organic phase waswashed with water (300×5) and dried (NaSO₄). After the solvent wasevaporated, the residue was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give 35.1 g(92%) of the pale yellow oil; ¹H NMR (CDCl₃) δ1.55(d, 3H), 2.40 (s, 3H),3.91 (q, 1H), 4.18 (m, 4H), 7.12 (m, 2H), 7.24 (m, 2H), 7.37 (d, 1H),7.66 (d, 1H), 7.70 (m, 4H); MS (ESI) m/z 429 (M+1).

EXAMPLE 2

Compound 11 (Scheme 2). Compound 11 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,3-propanediol (3). The resulting compound 11 was purified bycrystallization from dichloromethane and hexanes with a 92% yield. ¹HNMR (CDCl₃) 8 1.59 (d, 3H), 1.78 (m, 2H), 1.87 (br, 1H, D₂O ex), 3.53(t, 2H), 3.87 (q, 1H), 3.91 (s, 3H), 4.23 (t, 2H), 7.11 (d, 1H), 7.15(m, 1H), 7.41 (q, 1H), 7.66 (d, 1H), 7.69 (s, 1H), 7.71 (s, 1H); ¹³C NMR(CDCl₃) δ18.6, 31.8 45.7, 55.5, 59.2, 61.9, 77.0, 77.2, 77.5, 105.8,119.2, 126.1, 126.3, 127.4, 129.1, 129.4, 133.9,135.7,157.8, 175.3; andMS (ESI) m/z 289.4 (M+1).

Compound 19 (Scheme 2). Compound 19 was prepared as described above forthe preparation of compound 18, this time employing compound 11 andTsCl. Compound 19 was purified by crystallization from ether and hexanewith an yield of 95%; ¹H NMR (CDCl₃) δ1.54 (d, 3H), 1.91 (m, 2H), 2.42(s, 3H), 3.79 (q, 1H), 3.92 (s, 3H), 3.99 (t, 2H), 4.10 (t, 2H), 7.11 d,1H), 7.15 (q, 1H), 7.26 (d, 2H), 7.34 (d, 2H), 7.62(d, 1H,), 7.70 (m,4H); ¹³C NMR (CDCl₃) δ18.5, 21.8, 28.4, 45.5, 55.5, 60.6, 66.9, 105.8,119.2, 126.0, 126.3, 127.4, 128.0, 129.1, 129.5, 130.1, 133.1, 133.9,135.6, 145.0, 157.9, 174.5; MS (ESI) m/z 421.1 (M−1).

EXAMPLE 3

Compound 12 (Scheme 2). Compound 12 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,4-butanediol (4). Compound 12 was purified by crystallization fromdichloromethane and hexanes with a 90% yield; ¹H NMR (CDCl₃) δ1.48 (m,2H), 1.59 (d, 3H), 1.64 (m, 2H), 1.85 (s, 1H, D₂O, ex), 3.52 (t, 2H),3.85 (q, 1H), 3.89 (s, 3H), 4.10 (t, 2H), 7.10-7.15 (m, 2H), 7.42 (d,1H), 7.66-7.7- (m, 3H); MS (ESI) m/z 325.4 (M+Na).

Compound 20 (Scheme 2). Compound 20 was prepared as described above forthe preparation of compound 18, this time employing compound 12 andTsCl. The compound 20 was purified by crystallization from ether andhexane with an yield of 93%; ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.53-1.62 (m,4H), 2.43 (s, 3H), 3.82 (q, 1H), 3.92 (s, 3H), 3.94 (m, 2H), 4.02 (m,2H), 7.11-7.15 (m, 2H), 7.30 (d, 2h), 7.38 (d, 1H), 7.64 (d, 1H), 7.70(d, 2H), 7.75 (d, 2H); MS (ESI) m/z 457.5 (M+1).

EXAMPLE 4

Compound 13 (Scheme 2). Compound 13 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,5-pentanediol (5). After reaction, the reaction solution was washedwith water and the reaction solvent was then evaporated under highvacuum to give a quantitative yield of the compound 13. The compound wasused to make compound 21 without further purification; ¹H NMR (CDCl₃)δ1.28 (m, 2H), 1.46 (m, 2H), 1.55 (d, 3H), 1.59 (m, 2H), 3.51 (t, 2H),3.85 (q, 1H), 3.91 (s, 3H), 4.09 (t, 2H), 7.11-7.15 (m, 2H), 7.40 (q,1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 317.5 (M+1).

Compound 21 (Scheme 2). Compound 21 was prepared as described above forthe preparation of compound 18, this time employing compound 13 andTsCl. Compound 21 was purified by crystallization from ether and hexanewith a 95% yield; ¹H NMR (CDCl₃) δ1.24 (m, 2H), 1.48-1.58 (m, 4H), 1.59(d, 3H), 2.43 (s, 3H), 3.84 (q, 1H), 3.89 (t, 2H), 3.91 (s, 3H), 4.01(t, 2H),7.11-7.15 (m, 2H), 7.32 (q, 2H), 7.39 (q, 1H), 7.65 (d, 1H),7.70 (m, 2H), 7.75 (d, 2H); MS (ESI) m/z 471.7 (M+1).

EXAMPLE 5

Compound 14 (Scheme 2). Compound 14 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,6-hexanediol (6). After reaction, the reaction solution was washedwith water and the reaction solvent was then evaporated to give compound14 as a solid. The compound was used to make compound 22 without furtherpurification; ¹H NMR (CDCl₃) δ1.24 (m, 4H), 1.43 (m 2H), 1.56 (d, 3H),1.54 (m, 2H), 3.51 (t, 2H), 3.85 (q, 1H), 4.01 (m, 2H), 7.10-7.15 (m2H), 7.40 (q, 1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 331.7 (M+1).

Compound 22 (Scheme 2). Compound 22 was prepared as described above forthe preparation of compound 18, this time employing compound 14 andTsCl. Compound 22 was purified by column chromatography on a silica gelcolumn using dichloromethane as an eluent to give compound 22 as a paleyellow oil; ¹H NMR (CDCl₃) δ1.12-1.22 (m, 4H), 1.46-1.52 (m, 4H), 1.57(d, 3H), 2.43 (s, 3H), 3.84 (q, 1H), 3.92 (s, 3H), 3.93 (m, 2H), 4.03(m, 2H), 7.11-7.77 (m, 10H); MS (ESI) m/z 485.6 (M+1).

EXAMPLE 6

Compound 15 (Scheme 2). Compound 15 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) anddi(ethylene glycol) (7). After reaction, the reaction solution waswashed with water and the reaction solvent was then evaporated to givecompound 15. The compound was used to make compound 23 without furtherpurification; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.93 (br, 1H, D₂O ex), 3.43(t, 2H), 3.59 (t, 2H), 3.62 (t, 2H), 3.89 (q, 1H), 3.90 (s, 3H), 4.25(m, 2H), 7.11-7.15 (m, 2H), 7.40-7.42 (m, 1H), 7.70 (t, 3H); ¹³C NMR(CDCl₃) δ18.7, 45.6, 55.5 61.8, 64.0, 69.2, 72.4, 76.9, 77.2, 77.5,105,7, 119.2, 126.2, 126.4, 127.3, 129.0, 133.9, 135.7, 157.9, 174.8;MS(ESI) m/z 319.3 (M+1).

Compound 23 (Scheme 2). Compound 23 was prepared as described above forthe preparation of compound 18, this time employing compound 15 andTsCl. Compound 23 was purified by column chromatography on a silica gelcolumn using dichloromethane as an eluent to give the compound as a paleyellow oil with a 93% yield. ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.41 (s, 3H),3.43 (m, 2H), 3.48(m, 2H), 3.84 (q, 1H), 3.86 (s, 3H), 3.94 (t, 2H),4.10 (m, 2H), 7.10-7.13 (m, 2H), 7.29 (d, 2H), 7.39 (d, 1H), 7.65-7.75(m, 5H); ¹³C NMR (CDCl₃) δ18.6, 21.8, 45.5, 55.5, 63.9, 68.7, 69.27,69.27, 105.8, 119.2, 126.2, 126.4, 127.4, 128.1, 129.0, 129.4, 129.9,133.9, 145.0, 157.9, 174.7; MS (ESI) m/z 473.4 (M+1).

EXAMPLE 7

Compound 16 (Scheme 2). Compound 16 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,3-pentanediol (8). After reaction, the reaction solution was washedwith water and the reaction solvent was then evaporated to give compound15 with a 32% yield. The compound was used to make compound 24 withoutfurther purification; ¹H NMR, ¹³C NMR and MS are consistent with thestructure of compound 16.

Compound 24 (Scheme 2). Compound 24 was prepared as described above forthe preparation of compound 18, this time employing compound 16 andTsCl. The compound 24 was purified by column chromatography on a silicagel column using dichloromethane as an eluent to give the compound as apale yellow oil with a 82% yield. The ¹H NMR, ¹³C NMR and MS areconsistent with the structure of compound 24.

EXAMPLE 8

Compound 17 (Scheme 2). Compound 17 was prepared as described above forthe preparation of compound 10, this time employing naproxen (1) and1,4-cyclohexanediol (8). After reaction, the reaction solution waswashed with water and the reaction solvent was then evaporated to givecompound 17. Compound 17 was used to make compound 25 without furtherpurification; ¹H NMR (CDCl₃) δ1.30-1.45 (m, 6H), 1.56 (d, 3H), 1.80-1.98(m, 4H), 3.66 (m, 1H), 3.82 (q, 1H), 3.91 (s, 3H), 4.75 (m, 1H), 7.11 m,2H), 7.39 (d, 1H), 7.65-7.70 (m, 3H); ¹³C NMR (CDCl₃) δ18.7, 28.2, 28.5,32.1 32.2, 45.9, 55.5, 68.9, 72.0, 76.9, 77.2, 77.5, 105.8, 119.1,126.0, 126.4, 127.2, 129.1, 129.5, 133.8, 136.1, 157.8, 174.4; MS (ESI)m/z 351.4 (M+Na).

Compound 25 (Scheme 2). Compound 25 was prepared as described above forthe preparation of compound 18, this time employing compound 17 andTsCl. Compound 25 was purified by column chromatography on a silica gelcolumn using dichloromethane as an eluent to give the compound as a paleyellow oil with a 93% yield; ¹H NMR (CDCl₃) δ1.50-1.84 (m, 11H), 2.43(s, 3H), 3.80 (q, 1H), 3.92 (s, 3H), 4.51 (m, 1H), 4.78 (m, 1H),7.10-7.15 (m 2H), 7.26-7.39 (m, 3H), 7.61-7.75 (m, 5H); MS (ESI) m/z483.5 (M+H).

The syntheses described in Examples 9-14 are outlined in Scheme 3.

EXAMPLE 9

Compound 32 (Scheme 3). Compound 32 was prepared as described above forthe preparation of compound 10, this time employing ketoprofen (26) and1,3-propanediol (3). Compound 32 was purified by column chromatographyon a silica gel column using 200:1 CH₂Cl₂/MeOH as an eluent to givecompound 32 with a 50% yield. ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.82 (m 3H,1H, D₂O ex), 3.58 (m, 2H), 3.82(m, 1H), 4.25 (m 2H), 7.44-7.82 (m, 9H);MS (ESI) m/z 313.5 (M+H).

Compound 38 (Scheme 3). Compound 38 was prepared as described above forthe preparation of compound 18, this time employing compound 32 andTsCl. Compound 38 was purified by column chromatography on a silica gelcolumn using CH₂Cl₂ as an eluent to give the compound 38 as a colorlessoil with a 81% yield; ¹H NMR (CDCl₃) δ1.49 (d, 3H), 1.94 (m, 2H), 2.43(s, 3H), 3.72 (q, 1H), 4.01 (t, 2H), 4.12 (m, 2H), 7.31-7.78 (m, 13H);MS (ESI) m/z 467.3 (M+H).

EXAMPLE 10

Compound 33 (Scheme 3). Compound 33 was prepared as described above forthe preparation of compound 10, this time employing flurbiprofen (27)and 1,3-propanediol (3). After reaction, the reaction solution waswashed in water and the reaction solvent was then evaporated to give thecompound 33 with a quantitative yield. The compound 33 was used to makecompound 39 without further purification; ¹H NMR (CDCl₃) δ1.54 (d, 3H),1.79 (t, 1H, D₂O ex), 1.85 (m, 2H), 3.63 (m, 2H), 3.76 (q, 1H), 4.27 (t,2H), 7.11-7.16(m, 2H), 7.35-7.46 (m, 4H), 7.54 (d, 2H); MS (ESI) m/z325.4 (M+Na).

Compound 39 (Scheme 3). Compound 39 was prepared as described above forthe preparation of compound 18, this time employing compound 33 andTsCl. Compound 39 was purified by crystallization from ether/hexanesystem with a 79% yield; ¹H NMR (CDCl₃) δ1.50 (d, 3H), 1.96 (m, 2H),2.42 (s, 3H), 3.68 (q, 1H), 4.03 (t, 2H), 4.15 (t, 2H), 7.05-7.11 (m,2H), 7.25-7.54 (m, 8H), 7.76 (d, 2H); ¹³C NMR (CDCl₃) δ18.4, 21.8, 28.4,45.0, 50.8, 66.9, 115.2, 115.5, 123.68, 123.7, 127.9, 128.0, 129.2,130.1, 131.0, 133.1, 135.6, 141.75, 141.8, 145.1, 158.9, 160.9, 173.9;MS (ESI) m/z 479.4 (M+Na).

EXAMPLE 11

Compound 34 (Scheme 3). Compound 34 was prepared as described above forthe preparation of compound 10, this time employing ibuprofen (28) and1,3-propanediol (3). After reaction, the reaction solution was washed inwater and the reaction solvent was then evaporated to give compound 34with a quantitative yield. The compound 34 was used to make compound 40without further purification; ¹H NMR (CDCl₃) δ0.89 (d, 6H), 1.49 (d,3H), 1.79 (t, 2H), 1.78-1.85 (m, 1H), 1.95 (t, 1H, D₂O ex), 2.45 (d,2H), 3.53 (m, 2H), 3.71 (q, 1H), 4.22 (m, 2H), 7.09 (d, 2H), 7.26 (d,2H).

Compound 40 (Scheme 3). Compound 40 was prepared as described above forthe preparation of compound 18, this time employing compound 34 andTsCl. Compound 40 was purified by crystallization from ether/hexanesystem to give a white solid with a 96% yield; ¹³H NMR (CDCl₃) δ0.89 (d,6H), 1.44 (d, 3H), 1.81-1.92 (m, 3H), 2.44 (s, 3H), 3.61 (q, 1H), 3.99(t, 2H), 4.09 (t, 2H), 7.08 (d, 2H), 7.14 (d, 2H), 7.34 (d, 2H), 7.78(d, 2H); ¹³C NMR (CDCl₃) δ18.46, 21.80, 22.54, 28.39, 30.32, 45.16,60.39, 66.92, 127.23, 128.04, 129.50, 130.03, 133.12, 137.68, 140.76,145.00, 174.54; MS (ESI) m/z 441.5 (M+Na).

EXAMPLE 12

Compound 35 (Scheme 3). Compound 35 was prepared as described above forthe preparation of compound 10, this time employing diclofenac (29) and1,3-propanediol (3). After reaction, compound 35 was purified by columnchromatography on a silica gel column using 200:1 CH₂Cl₂/MeOH as aneluent to give the compound 35 as a white solid with a 56% yield. ¹H NMR(CDCl₃) δ1.89 (m, 3H, 1H D₂O ex), 3.66 (t, 2H), 3.83 (s, 3H), 4.31 (t,2H), 6.55 (d, 1H), 6.87 (br, 1H), 6.94-7.00 (m, 2H), 7.11-7.14 (m, 1H),7.22-7.26 (m, 1H), 7.34 (d, 2H); MS (ESI) m/z 376.3 (M+Na).

Compound 41 (Scheme 3). Compound 41 was prepared as described above forthe preparation of compound 18, this time employing compound 35 andTsCl. Compound 41 was purified by column chromatography on a silica gelcolumn using CH₂Cl₂ as an eluent to give the compound 41 as a paleyellow oil and the yield was 89%; ; H NMR (CDCl₃) δ2.02 (m, 2m,), 2.43(s, 3H), 3.73 (s, 2H), 4.09 (t, 21), 4.17 (t, 2H), 6.53 (d, 1H), 6.99(s, 1H), 6.93-7.00 (m, 21), 7 .12 (t, 1H), 7.18 (d, 1H), 7.23 (d, 11),7.31-7.35 (m, 3H), 7.78 (d, 21H); MS (ESI) m/z 508.3 (M).

EXAMPLE 13

Compound 36 (Scheme 3). Compound 36 was prepared as described above forthe preparation of compound 10, this time employing carprofen (30) and 1,3-propanediol (3). After reaction, compound 36 was purified by columnchromatography on a silica gel column using 200:1 CH₂Cl₂/MeOH as aneluent to give the compound 36 as a colorless oil with a 54% yield. ¹HNMR (CDCl₃) δ1.59 (d, 3H), 1.74 (br, 1H, D₂O ex), 1.80 (m, 2H),3.53-3.56 (m, 2H), 3.88 (q, 1H), 4.22-4.28 (m, 2H), 7.17 (d, 1H),7.29-7.35 (m, 3H), 7.94-7.98 (m, 2H), 8.14 (br, 1H); ¹³C NMR (CDCl₃)δ18.99, 31.84, 46.17, 59.42, 62.10, 109.70, 111.79, 119.79, 120.21,120.87, 121.92, 124.49, 125.22, 126.09, 138.24, 139.37, 140.55, 175.39;MS (ESI) m/z 332.2 (M+H).

Compound 42 (Scheme 3). Compound 42 was prepared as described above forthe preparation of compound 18, this time employing compound 36 andTsCl. Compound 42 was purified by column chromatography on a silica gelcolumn using CH₂Cl₂as an eluent to give the compound 42 as a sticky oiland the yield was 90%; ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.91 (m, 2H), 2.39(s, 3H), 3.83 (q, 1H), 3.97 (t, 2H), 4.09-4.18 (m, 2H), 7.10 (d, 2H),7.21(d, 2H), 7.32 (s, 2H), 7.38 (s, 1H)7.65 (d, 2H), 7.91 (d, 1H), 7.98(s, 1H), 8.54 (s, 1H); ¹³C NMR (CDCl₃) δ18.83, 21.77, 28.32, 46.08,60.59, 57.04, 109.97, 111.97, 119.58, 120.06, 120.69, 121.77, 124.38,125.00, 125.99, 127.95, 129.22, 130.06, 132.90, 138.38, 139.19,140.69,145.15,174.59; MS (ESI) m/z 486.3 (M+H).

EXAMPLE 14

Compound 37 (Scheme 3). Compound 37 was prepared as described above forthe preparation of compound 10, this time employing indomethacin (31)and 1,3-propanediol (3). After reaction, compound 37 was purified bycolumn chromatography on a silica gel column using 200:1; 100:1CH₂Cl₂/MeOH as an eluents to give the compound 37 as a pale yellow oilwith a 49% yield. ¹H NMR, ¹³C NMR and MS are consistent with thestructure of compound 37.

Compound 43 (Scheme 3). Compound 43 was prepared as described above forthe preparation of compound 18, this time employing compound 37 andTsCl. The compound 43 was purified by column chromatography on a silicagel column using hexanclethyl acetate (3:1) as an eluent to give thecompound 43 as a pale yellow oil and the yield was 71%; ¹H NMR (CDCl₃)δ1.97 (m, 2H), 2.36 (s, 3H), 2.44 (s, 3H), 3.63 (s, 2H), 3.83 (s, 3H),4.05 (t, 2H), 4.15 (t, 2H), 6.66-6.68 (m, 1H), 6.87 (d, 1H), 6.93 (d,1H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H), 7.75 (d, 2H); MS (ESI)m/z 592.0 (M+Na)

The syntheses described in Examples 15 and 16 are outlined in Scheme 4.

EXAMPLE 15

Compound 46 (Scheme 4). Compound 46 was prepared as described above forthe preparation of compound 18, this time employing compound 11 and 44.The compound 46 was purified by crystallization from ether/hexane systemto give the compound 46 as a white solid. The yield was 95%; ¹H NMR(CDCl₃) δ1.58 (d, 3H), 2.00 (m, 2H), 2.73 (s, 3H), 3.87 (q, 1H), 3.90(s, 3H), 4.10 (t, 2H), 4.18 (t, 2H), 7.10-7.15 (m, 2H), 7.39 (d, 1H),7.66-7.71 (m, 3H); ¹³C NMR (CDCl₃) δ18.46,28.55, 37.03, 45.56, 55.47,55.50, 60.38, 66.36, 105.75, 119.32, 126.09, 126.27, 127.44, 129.06,129.41, 133.89, 135.68,157.91, 174.59; MS (ESI) m/z 388.5 (M+Na).

EXAMPLE 16

Compound 47 (Scheme 4). Compound 47 is prepared as described above forthe preparation of compound 18, this time employing compound 11 andcompound 45. The compound is purified by crystallization and the yieldwas 70-90%. The ¹H NMR, ¹³C NMR and MS are consistent with the structureof compound 47.

The syntheses described in Examples 17 and 18 are outlined in Scheme 5.

EXAMPLE 17

Compound 50 (Scheme 5). To a solution of naproxen (1) (1.15 g, 5 mmol),compound 48 (0.62 g, 5 mmol) and dimethylamino pyridine (DMAP) (0.12 g,1 mmol) was added dicyclohexyldicarbodiimide (DCC) (1.03 g, 5 mmol) at0° C. The resulting solution was stirred at 0° C. for 1.5 h. Afterreaction, the solid was filtered off and the solvent was evaporated. Theresidue was washed with ether to give 1.4 g (83%) of compound 50 as awhite solid; ¹H NMR (CDCl₃) δ1.59 (d, 3H), 2.38 (s, 3H), 3.17 (m, 2H),3.87 (q, 1H), 3.92 (s, 3H), 4.43 (m, 1H), 4.59 (m, 1H), 7.10 (d, 1H),7.15 (m, 1H), 7.33 (m, 1H), 7.67 (d, 1H), 7.70 (m, 2H); MS (ES) m/e358.2 (M+Na).

EXAMPLE 18

Compound 51 (Scheme 5). Compound 51 was prepared as described above forthe preparation of compound 50, this time employing compound 1 (1.15 g,5mmol) and 49 (1.16 g, 5 mmol). The compound was purified by columnchromatography on a silica gel column using 1:1 hexanes/ethyl acetate aseluent to give 0.91 g of compound 51 as a pale yellow oil; ¹H NMR(CDCl₃) δ1.45 (d, 3H), 3.48 (m, 2H), 3.59 (q, 1H), 3.92 (s, 3H), 4.47(m, 2H), 7.10 (d, 1H), 7.18 (m, 2H), 7.45 (s, 1H), 7.49 (t, 1H), 7.65(t, 2H), 8.06 (q, 1H), 8.28 (q, 1H), 8.68 (s, 1H); ¹³C NMR (CDCl₃)δ18.8, 45.2, 55.4, 55.5, 57.9, 105,8, 123.6, 125.9, 127.5, 128.4, 129.0,129.3, 130.8, 133.7, 133.9, 134.9, 141.5, 148.4, 158.0, 174.0.

The syntheses described in Examples 19-21 are outlined in Scheme 6.

EXAMPLE 19

Compound 55 (Scheme 6). A mixture of compound 19 (2.2 g, 5 mmol),compound 52 (0.57 g, 6 mmol) and K₂CO₃ (3.45 g, 25 mmol) in 50 ml ofdimethyl formamide (DMF) was stirred for a week. The reaction solutionwas poured into 100 ml of water and extracted with CH₂Cl₂. The organicphase was washed with water (50×5) and dried (Na₂SO₄). The solvent wasevaporated and the residue was purified by column chromatography on asilica gel column using 3:1 hexane/ethyacetate as an eluent to give 0.3g (16%) of compound 55 as a pale yellow oil; ¹H NMR (CDCl₃) δ1.60 (d,3H), 2.38 (s, 3H), 3.17 (m, 2H), 3.87 (q, 1H), 3.92 (s, 3H), 4.45 (m,1H), 4.59 (m, 1H), 7.10 (s, 1H), 7.14-7.16 (q, 1H), 7.32-7.35 (q, 1H),7.62 (s, 1H), 7.67-7.71 (m, 2H); MS (ESI) m/z 358.2 (M+Na).

EXAMPLE 20

Compound 56 (Scheme 6). Compound 56 was prepared as described above forthe preparation of compound 55, this time employing compound 19 andcompound 53. The compound was purified by column chromatography on asilica gel column using CH₂Cl₂ as an eluent to give compound 56 as apale yellow oil (33%). ¹H NMR (CDCl₃) δ1.54 (d, 3H), 1.72 (m, 2H), 2.83(m, 2H), 3.80 (q, 1H), 3.92 (s, 3H), 4.10 (t, 2H),7.07-8,10 (m, 10H); MS(ESI) m/z 442.3 (M+H).

EXAMPLE 21

Compound 57 (Scheme 6). Compound 57 was prepared as described above forthe preparation of compound 55, this time employing compound 19 andcompound 54. The compound was purified by column chromatography on asilica gel column using CH₂Cl₂ as an eluent to give compound 57 as apale yellow oil (11%). ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.80 (m, 2H), 3.03(m 2H),3.86 (m, 1H), 4.13 (m, 2H), 7.07-7.93 (m, 10H), MS (ESI) m/z473.4 (M+H).

The syntheses described in Examples 22 and 23 are outlined in Scheme 7.

EXAMPLE 22

Compound 60 (Scheme 7). Compound 60 is prepared as described above forthe preparation of compound 50, this time employing naproxen 1 andcompound 58. After reaction the compound is purified by columnchromatography on a silica gel column to give the compound 60 in a yieldfrom 75-95%.

EXAMPLE 23

Compound 61 (Scheme 7). Compound 61 is prepared as described above forthe preparation of compound 50, this time employing naproxen 1 andcompound 59. After reaction, the compound is purified by columnchromatography on a silica gel column to give compound 61 in a yieldfrom 75-95%.

The syntheses described in Examples 24 and 25 are outlined in Scheme 8.

EXAMPLE 24

Compound 63 (Scheme 8). Compound 63 is prepared as described above forthe preparation of compound 50, this time employing naproxen (1) andcompound 62. After reaction, the compound is purified by columnchromatography on a silica gel column to give compound 63 in a yield of75-95%.

Compound 66 (Scheme 8). Compound 66 is prepared as described above forthe preparation of compound 18, this time employing compound 63 andcompound 64.

EXAMPLE 25

Compound 67 (Scheme 8). Compound 67 is prepared as described above forthe preparation of compound 18, this time employing compound 63 andcompound 65.

The syntheses described in Examples 26 and 27 are outlined in Scheme 9.

EXAMPLE 26

Compound 70 (Scheme 9). Compound 70 is prepared as described above forthe preparation of compound 60, this time employing compound 1 andcompound 68.

EXAMPLE 27

Compound 71 (Scheme 9). Compound 71 is prepared as described above forthe preparation of compound 60, this time employing compound 1 andcompound 69.

The synthesis described in Example 28 is outlined in Scheme 10.

EXAMPLE 28

Compound 73 (Scheme 10). Compound 73 is prepared as described above forthe preparation of compound 60, this time employing compound 1 andcompound 72.

The synthesis described in Example 29 is outlined in Scheme 11.

EXAMPLE 29

Compound 75 (Scheme 11). To a solution of naproxen 1 (1.15 g, 5.0 mmol)and 1,3-dicyclohexylcarbodiimide (DCC) (1.03 g, 5mmol) in 180 ml ofanhydrous tedrahydrofuran (THF) was added4-(2-aminoethyl)benzenesulfonamide 74 (1.1 g, 5.5 mmol) at rt. Theresulting mixture was stirred overnight. The resulted solid was filteredoff and the solvent was evaporated. The residue was partially dissolvedin ethyl acetate and filtered to remove more solid. The filtrate wasevaporated and the residue was purified by flash chromatography on asilica gel column using CH₂Cl₂ and 100:1 CH₂Cl₂-MeOH as eluents to give0.1 g (5%) of the compound 75 as a white solid; ¹H NMR (DMSO-d₆) δ1.38(d, 3H), 2.73 (m, 3H, 1H, ex D₂O), 3.68 (q, 1H), 3.86 (s, 3H), 7.13-8.08(m, 12H, 2H, ex D₂O); MS (ESI) m/z 413.1 (M +H)⁺(C₂₂H₂₅N₂O₄S requires413.5).

The syntheses described in Examples 30 and 31 are outlined in Scheme 12.

EXAMPLE 30

Compound 78 (Scheme 12). To a solution of naproxen 1 (1.15 g, 5 mmol)and benzenesulfonyl hydrazide 76 (0.86 g, 5 mmol) in 50 ml of CH₂Cl₂ wasadded DCC (1.03 g, 5 mmol) at rt. The resulting solution was stirred atrt for 26 h. The resulted solid was filtered off and the filtrate waswashed with 5% Na₂CO₃ solution, 0.5N HCl solution and water. The organicphase was dried with anhydrous sodium sulfate (Na₂SO₄) and concentrated.The residue was purified by flash chromatography on a silica gel columnusing 5:1 and 2:1 hexanes-EtOAc as eluents to give 1.44 g (75%) of thecompound 78 as a white solid; ¹H NMR (CDCl₃) δ1.37 (d, 3H), 3.54 (q,1H), 3.94 (s, 3H), 7.12-7.77 (m, 13H, 2H, ex D₂O); MS (ESI) m/z 385.0(M+H)⁺ (C₂₀H₂₁N₂O₄S requires 385.1).

EXAMPLE 31

Compound 79 (Scheme 12). Compound 79 was prepared by the similarprocedure as described above for compound 78 from4-methoxybenzenesulfonyl hydrazide 77 (1.01 g, 5 mmol), naproxen 1 (1.15g, 5 mmol) and DCC (1.03 g, 5 mmol). The compound was purified by flashchromatography on a silica gel column using 200:1 CH₂Cl₂-MeOH as aneluent to give 0.69 g (33%) of the compound 79 as a white solid; ¹H NMR(CDCl₃) δ1.38 (d, 3H), 3.57 (q, 1H), 3.68 (s, 3H), 3.92 (s, 3H),6.60-8.13 (12H, 2H ex D₂O); MS (ESI) m/z 415.7 (M+H)⁺ (C₂₁H₂₃N₂O₅Srequires 415.2).

The syntheses described in Examples 32-35 are outlined in Scheme 13.

EXAMPLE 32

Compound 84 (Scheme 13). To a solution of naproxen 1 (1.15 g, 5 mmol)and 2-(methylthio)ethanol 80 (0.46 g, 5 mmol) and 4-(dimethylamino)pyridine (DMAP) (0.12 g, 1 mmol) in 50 ml of CH₂Cl₂ wasadded DCC (1.03 g, 5 mmol) at 0° C. The resulting solution was stirredat 0° C. for 2 h. The solid was filtered off and the solvent wasevaporated. The residue was partially dissolved in EtOAc and the mixturewas filtered to remove more solid. The filtrate was washed with water(50×2), dried (Na₂SO₄) and concentrated. Recrystallization of the crudeproduct from hexanes provided 0.96 g of the compound 84 as a whitecrystal; ¹H NMR (CDCl₃) δ1.59 (d, 3H), 2.05 (s, 3H), 2.65 (m, 2H), 3.86(q, 1H), 3.91 (s, 3H), 4.25 (m, 2H), 7.11-7.25 (m, 2H), 7.41 (d, 1H),7.67-7.71 (m, 3H); ¹³C NMR (CDCl₃) δ15.9, 16.8, 32.6, 45.6, 55.5, 63.7,105.8, 119.2, 126.2, 126.4, 127.4, 129.1, 129.4, 133.9, 135.7, 157.9,174.7; MS (ESI) m/z 327.4 (M+Na)⁺ (C₁₇H₂O₃SNa requires 327.1).

Compound 50 (Scheme 13). To a solution of compound 84 (0.09 g, 0.3 mmol)in 3 ml of acetone was added m-chloroperoxybenzoic acid (m-CPBA) (0.25g, 1.5 mmol). The resulting solution was stirred at 0° C. for 3 h. Asolution of Na₂SO₃ was added to quench the reaction and then more waterwas added. The resulted mixture was filtered and washed with methanol togive a compound which has the identical ¹H NMR and MS properties tocompound 50 produced by the procedure set forth in Example 17 above.

EXAMPLE 33

Compound 85 (Scheme 13). Compound 85 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (6.9 g, 30mmol), methylthiopropanol 81 (3.06 ml, 3.18 g, 30 mmol), DMAP (0.72 g, 6mmol) and DCC (6.18 g, 30 mmol). The compound was purified byrecrystallization from hexanes to give 6.7 g (70%) of the compound 85 asa white crystal; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.85 (m, 2H), 1.97 (s,3H), 2.39 (t, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.17 (m, 2H), 7.11-7.15(m, 2H), 7.39-7.41 (m,1H), 7.66-7.71 (m, 3H); MS (ESI) m/z 441.5(M+Na)⁺. (C₁₈H₂₂O₃SNa requires 441.2).

Compound 88 (Scheme 13). Compound 88 was prepared by the similarprocedure as described above for compound 50 from compound 85 (1.27 g, 4mmol) and m-CPBA (3.4 g, 20 mmol). The product was purified byrecrystallization from EtOAc-hexanes to give 1.1 g (80%) of the compound88 as a white powder; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.08 (m, 2H), 2.59(s, 3H), 2.75 (m, 2H), 3.86 (q, 1H), 3.91 (s, 3H), 4.16 (m, 1H), 4.26(m, 1H), 7.11-7.16 (m, 2H), 7.37-7.39 (m, 1H), 7.66 (s, 1H), 7.70-7.73(m, 2H); MS (ESI) m/z 373.3 (M+Na)⁺ (C₁₈H₂₂O₃SNa requires 373.1).

EXAMPLE 34

Compound 86 (Scheme 13). Compound 86 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (6.9 g, 30mmol), methylthiobutanol 82 (3.6 g, 30 mmol), DCC (6.18 g, 30 mmol) andDMAP (0.72 g, 6 mmol). The product was purified by recrystallizationfrom hexanes to give 7.3 g (73%) of the compound 86 as a white solid; ¹HNMR (CDCl₃) δ1.54 (m, 2H), 1.58 (d, 3H), 1.67 (m, 2H), 1.96 (s, 3H),2.40 (t, 2H), 3.85 (q, 1H), 3.89 (s, 3H), 4.09 (t, 2H), 7.10-7.15 (m,2H), 7.39-7.41 (q, 1H), 7.66-7.70 (t, 3H); ¹³C NMR (CDCl₃) δ15.35,18.59, 25.48, 27.74, 33.72, 45,61, 55.3, 64.37, 105.70, 119.08, 126.02,126.32, 127.24, 129.04, 129.37, 133.80, 135.85,157.74, 174.76; MS (ESI)m/z 355.3 (M+Na)⁺ (C₁₉H₂₄O₃SNa requires 355.1).

Compound 89 (Scheme 13). Compound 89 was prepared by the similarprocedure as described above for compound 50 from compound 86 (1.33 g, 4mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone. The product waspurified by recrystallization from CH₂Cl₂-hexane to give 1.13 g ( 78%)of the compound 89 as a pale yellow solid; ¹H NMR (CDCl₃) δ1.57 (d, 3H),1.73 (m, 4H), 2.56 (s, 3H), 2.82 (m, 2H), 3.65 (q, 1H), 3.90 (s, 3H),4.08 (m, 1H), 4.15 (m, 1H), 7.10-7.15 (m, 2H), 7.38-7.40 (q, 1H), 7.65(s, 1H), 7.70 (d, 2H); ¹³C NMR (CDCl₃) δ18.5, 19.4, 27.5, 40.2, 45.6,54.2, 55.5, 63.7, 105.8, 119.4, 126.1, 126.3, 127.4, 129.1, 129.4,133.9, 135.8, 157.9, 174.7; MS (ESI) m/z 387.5 (M+Na)⁺ (C₁₉H₂₄O₅SNarequires 3 87.5).

EXAMPLE 35

Compound 87 (Scheme 13). Compound 87 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (1.15 g, 5mmol), 2-(phenylthio)ethanol 83 (0.77 g, 5 mmol), DCC (1.03 g, 5 mmol)and DMAP (0.12 g, 1 mmol) in 50 ml of CH₂Cl₂. The product was purifiedby recrystallization from hexanes to give 1.0 g (56%) of the compound 87as a white powder; ¹H NMR (CDCl₃) δ1.56 (d, 3H), 3.10 (m, 2H), 3.83 (q,1H), 3.91 (s, 3H), 4.25 (m, 2H), 7.11-7.40 (m, 8H), 7.65-7.70 (m, 3H);¹³C NMR (CDCl₃) δ18.7, 32.5, 45.6, 55.5, 63.4, 105.8, 119.2, 126.2,126.4, 126.8, 127.4, 129.1, 129.2, 129.5, 130.1, 133.9, 135.3, 135.7,157.9, 174.7; MS (ESI) m/z 389.5 (M+Na)⁺ (C₂₂H₂₂O₂SNa requires 389.2).

Compound 90 (Scheme 13). Compound 90 was prepared by the similarprocedure as described above for compound 50 from compound 87 (1.46 g, 4mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone. The product waspurified by recrystallization from CH₂Cl₂-hexane to give 1.2 g (75%) ofthe compound 90 as a white solid; ¹H NMR (CDCl₃) δ1.46 (d, 3H), 3.40 (m,2H), 3.59 (q, 1H), 3.92 (s, 3H), 4.33 (m, 1H), 4.45 (m, 1H), 7.11-7.85(m, 11H); ¹³C NMR (CDCl₃) δ18.6, 45.2, 55.2, 55.5, 58.1, 105.8, 119.3,126.2, 127.4, 128.3, 129.1, 129.4.129.5, 133.9, 134.1, 135.1, 139.5,158.0, 174.2; MS (ESI) m/z 399.4 (M+H)⁺ (C₂₂H₂₃O₅S requires 399.5)

The synthesis described in Example 36 is outlined in Scheme 14.

EXAMPLE 36

Compound 92 (Scheme 14). Compound 92 was prepared by the similarprocedure as described above for compound 84 from methylthiobenzenealcohol 91 (4.6 g, 30 mmol), naproxen 1 (6.9 g, 30 mmol), DCC (6.18 g,30 mmol) and DMAP (0.72 g, 6 mmol). The product was purified byrecrystallization from CH₂Cl₂-hexanes to give 8.6 g (78%) of thecompound 92 as a white crystal; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.45 (s,3H), 3.89 (q, 1H), 3.92 (s, 3H), 5.05 (q, 2H), 7.11-7.16 (m, 6H),7.37-7.39 (m, 1H), 7.63-7.70 (m, 3H); ¹³C NMR (CDCl₃) δ15.9, 18.7, 45.7,55.5, 66.3, 105.8, 119.2, 126.2, 126.5, 126.7, 127.3, 128.9, 129.1,129.5, 132.9, 133.9, 135.7, 138.8, 157.9, 174.6; MS (ESI) m/z 389.4(M+Na)⁺ (C₂₂H₂₂O₃Sna requires 389.5)

Compound 93 (Scheme 14). Compound 93 was prepared by the similarprocedure as described above for compound 50 from compound 92 (1.1 g, 3mmol), m-CPBA (1.34 g, 7.5 mmol) in 30 ml of acetone. The product waspurified by flash chromatography on a silica gel column using CH₂Cl₂ asan eluent to give 1.0 g (85%) of the compound 93 as a white solid; ¹HNMR (CDCl₃) δ1.61 (d, 3H), 2.99 (s, 3H), 3.92 (s, 3H), 3.93 (q, 1H),5.18 (q, 2H), 7.12-7.16 (m, 2H), 7.34-7.39 (m, 3H), 7.65-7.71 (m, 3H),7.81 (d, 2H); ¹³C NMR (CDCl₃) δ18.5, 44.7, 45.6, 55.5, 65.3, 105.8,119.4, 126.2, 126.3, 127.5, 127.8, 128.3, 129.1, 129.4, 133.9, 135.3,140.2, 142.5, 158.0, 174.4; MS (ESI) m/z 398.9 M⁺ (C₂₂H₂₂)₅S requires398.5)

The synthesis described in Example 37 is outlined in Scheme 15.

EXAMPLE 37

Compound 95 (Scheme 15). A mixture of 2,2′-sulfonyldiethanol 94 (12.5ml, 60% in H₂O, 9.25 g, 60 mmol) and CHCl₃ was heated to reflux toremove the water and then naproxen 1 (4.6 g, 20 mmol) and4-toluenesulfonic acid (TsOH) (0.25 g, 1.3 mmol) were added to the abovemixture. The resulting mixture was continued to reflux for 6 h. Thereaction mixture was washed with water twice, 10% Na₂CO₃ solution twiceand then water once. The organic phase was dried (Na₂SO₄) and thesolvent was evaporated. The crude product was recrystallized fromCHCl₃-hexanes to give 0.41 g of the compound 95 as a white powder; ¹HNMR (CDCl₃) δ1.60 (d, 3H), 1.85 (bs, 1H, ex D₂O), 2.51-2.56 (m, 1H),2.62-2.67 (m, 1H), 3.25-3.28 (m, 2H), 3.48-3.51 (m, 2H), 3.88 (q, 1H),3.92 (s, 3H), 4.41-4.46 (m, 1H), 4.56-4.61 (m, 1H), 7.11 (d, 1H),7.15-7.18 (q, 1H), 7.35-7.36 (q, 1H), 7.65 (s, 1H), 7.69-7.74 (m, 2H);¹³C NMR (CDCl₃) δ18.3, 45.6, 54.0, 55.5, 55.6, 56.2, 56.3, 58.6, 105.8,119.8, 126.1, 126.4, 127.7, 129.0, 133.9, 135.2, 158.2, 173.9; MS (ESI)m/z 389.1 (M+Na)⁺ (C₁₈H₂₂O₆Sna requires 389.1)

The syntheses described in Examples 38-45 are outlined in Scheme 16.

EXAMPLE 38

Compound 102 (Scheme 16). A solution of compound 12 (3.02 g, 10 mmol)and methanesulfonyl chloride 96 (1.55 ml, 2.29 g, 20 mmol) in 10 ml ofpyridine was stirred at 0° C. for 2 h. 100 ml of water was added and theresulting mixture was filtered and the solid was washed with water fivetimes. The compound was purified by rerecrystallization fromCH₂Cl₂-hexanes to give 3.0 g (79%) of the compound 102 as a white solid;¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.67 (m, 4H), 2.88 (s, 3H), 3.85 (q, 1H),3.91 (s, 3H), 4.10 (m, 4H), 7.11-7.15 (m, 2H), 7.38-7.40 (q, 1H),7.65-7.71 (s, 3H), ¹³C NMR (CDCl₃) δ18.6, 24.9, 25.9, 37.5, 45.6, 55.5,63.9, 69.4, 105.8, 119.2, 126.1, 126.4, 127.4, 129.1, 129.4, 133.9,136.8, 157.9, 174.8; MS (ESI) m/z 403.6 (M+Na)⁺ (C₁₉H₂₄O₆Sna requires403.5).

EXAMPLE 39

Compound 103 (Scheme 16). Compound 103 was prepared by the similarprocedure as described above for compound 102 from compound 13 (4.74 g,15 mmol) and compound 96 (2.31 ml, 3.43 g, 30 mmol). The product waspurified by recrystallization from CH₂Cl₂-hexanes to give 5.1 g (86%) ofthe compound 103 as a white solid; ¹H NMR (CDCl₃) δ1.30 (m, 2H), 1.58(d, 3H), 1.62(m, 4H), 2.9 (s, 3H), 3.89 (q, 1H), 3.91 (s, 3H), 4.02-4.11(m, 4H), 7.11-7.15 (m, 2H), 7.39 (d, 1H), 7.66-7.71 (m, 3H); ¹³C NMR(CDCl₃) δ18.5, 22.1, 28.1, 28.8, 37.4, 45.7, 55.5, 64.5, 69.8, 105.8,119.2, 126.1, 126.4, 127.3, 129.4, 133.9, 135.9, 157.9, 174.9; MS (ESI)m/z 395.1 (M+H)⁺ (C₂₀H₂₇O₆S requires 395.1).

EXAMPLE 40

Compound 104 (Scheme 16). Compound 104 was prepared by the similarprocedure as described above for compound 102 from compound 14 (3.3 g,10 mmol) and compound 96 (1.55 ml, 2.31 g, 20 mmol). The product waspurified by recrystallization from CH₂Cl₂-hexanes to give 1.72 g (42%)of the compound 104 as a white solid; ¹H NMR (CDCl₃) δ1.21-1.31 (m, 4H),1.53-1.61 (m, 7H), 2.95 (s, 3H), 3.89 (q, 1H), 3.91 (s, 3H), 4.04-4.12(m, 4H), 7.12-7.15 (m, 2H), 7.40 (q, 1H), 7.69 (t, 3H); MS (ESI) m/z431.4 (M+Na)⁺ (C₂₁H₂₈O₆Sna requires 431.5).

EXAMPLE 41

Compound 105 (Scheme 16). Compound 105 was prepared by the similarprocedure as described above for compound 103 from compound 12 (1.51 g,5 mmol) and compound 100 (0.94 ml, 1.28 g, 10 mmol). The product waspurified by flash chromatography on a silica gel column using CH₂Cl₂ asan eluent to give 1.45 g (74%) of the compound 105 as a pale yellow oil;¹H NMR (CDCl₃) δ1.35 (t, 3H), 1.57(d, 3H), 1.68 (m, 4H), 3.01(q, 2H),3.84 (q, 1H), 3.90 (s, 3H), 4.11 (m, 4H); MS (ESI) m/z 417.4 (M+Na)⁺(C₂₀H₂₆O₆Sna requires 417.5).

EXAMPLE 42

Compound 106 (Scheme 16). Compound 106 was prepared by the similarprocedure as described above for compound 102 from compound 12 (1.51 g,5 mmol) and compound 97 (1.27 ml, 1.76 g, 10 mmol). The product waswashed with water and dried to give 1.9 g (86%) of the compound 106 as apale yellow oil; ¹H NMR (CDCl₃) δ1.53 (d, 3H), 1.55-1.63 (m, 4H), 3.81(q, 1H), 3.91 (s, 3H), 3.94-4.03 (m, 4H), 7.11-7.15 (m, 2H), 7.36 (d,1H), 7.51(m, 2H), 7.63 (m, 2H), 7.69 (d, 2H), 7.85 (d, 2H); MS (ESI) m/z443.6 (M+H)⁺ (C₂₄H₂₇O₆S requires 443.5).

EXAMPLE 43

Compound 107 (Scheme 16). Compound 107 was prepared by the similarprocedure as described above for compound 102 from compound 12 (1.51 g,5 mmol) and compound 98 (1.55 ml, 2.45 g, 10 mmol). The product waspurified by flash chromatography on a silica gel column using CH₂Cl₂ asan eluent to give 1.12 g (44%) of the compound 107 as a white solid; ¹HNMR (CDCl₃) δ1.56 (d, 3H), 1.60-1.63 (m, 4H), 3.82 (q, 1H), 3.90 (s,3H), 4.00-4.06 (m, 4H), 7.11-7.15 (m, 2H), 7.36-7.38 (q, 1H), 7.64-7.71(m, 4H), 7.89 (d, 1H), 8.04 (d, 1H), 8.15 (s, 1H); ¹³C NMR (CDCl₃)δ18.5, 24.8 25.7, 45.6, 55.5, 63.7, 70.8, 105.8, 119.2, 125.06, 125.09,126.3, 127.4, 129.1, 129.4, 130.3, 130.6, 131.2, 132.1, 133.9, 135.8,137.6, 157.9, 174.8; MS (ESI) m/z 533.3 (M+Na)⁺ (C₂₅H₂₅F₃O₆Sna requires533.5).

EXAMPLE 44

Compound 108 (Scheme 16). Compound 108 was prepared by the similarprocedure as described above for compound 102 from compound 12 (1.51 g,5 mmol) and compound 99 (2.06 g, 10 mmol). The product was purified byrecrystallization from CH₂Cl₂-hexanes to give 1.44 g (61%) of compound108 as a white crystal; ¹H NMR and MS spectra are consistence with thecompound 108.

EXAMPLE 45

Compound 109 (Scheme 16). Compound 109 was prepared by the similarprocedure as described above for compound 102 from compound 13 (1.58 g,5 mmol) and compound 101 (2.21 g, 10 mmol). The product was purified byflash chromatography on a silica gel column using CH₂Cl₂ as an eluent togive 1.5 g (67%) of the compound 109 as a pale yellow oil; ¹H NMR(CDCl₃) δ1.21-1.26 (m, 2H), 1.50-1.59 (m, 7H), 3.83 (q, 1H), 3.91 (s,3H), 3.89-4.08 (m, 4H), 7.11-7.26 (m, 2H), 7.37-7.40 (m, 1H), 7.63-7.70(m, 3H), 8.02 (d, 2H), 8.35 (d, 2H); MS (ESI) m/z 524.6 (M+Na)⁺(C₂₅H₂₇NO₈Sna requires 524.6).

The syntheses described in Examples 46 and 47 are outlined in Scheme 17.

EXAMPLE 46

Compound 111 (Scheme 17). A mixture of compound 20 (4.56 g, 10 mmol),methanesulfonamide 110 (1.9 g, 20 mmol, 2 equiv) and K₂CO₃ (6.9 g, 50mmol, 5 equiv) in 100 ml of acetonitril (CH₃CN) was heated to reflux for26 h. The solvent was evaporated and the residue was dissolved andshaken well in water and EtOAc. The two phases were separated and theorganic phase was washed with water three times, dried (Na₂SO₄) andconcentrated. The crude product was purified by recrystallization fromCH₂Cl₂-hexanes to give 2.53 g (67%) of the compound 111 as an yellowsolid; ¹H NMR (CDCl₃) δ1.38-1.42 (m, 2H), 1.53-1.63 (m, 2H), 1.58 (d,3H), 2.77 (s, 3H), 2.92-2.96 (m, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 3.99(bs, 1H, ex D₂O), 4.03-4.07 (m, 1H), 4.11-4.16 (m, 1H), 7.12-7.16 (m,2H), 7.38-7.40 (d, 1H), 7.66 (s, 1H), 7.71 (d, 2H); MS (ESI) m/z 402.5(M+Na)⁺ (C₁₉H₂₅NO₅SNa requires 402.5).

EXAMPLE 47

Compound 112 (Scheme 17). Compound 112 was prepared by the similarprocedure as described above for compound 111 from compound 22 (2.42 g,5 mmol) and compound 110 (0.57 g, 6 mmol, 1.2 equiv). The product waspurified by recrystallization from CH₂Cl₂-hexanes to give 0.9 g (45%) ofthe compound 112 as a powder; ¹H NMR (CDCl₃) δ1.17-1.22 (m, 4H),1.33-1.37 (m, 2H), 1.56 (d, 3H), 1.52-1.60 (m, 2H), 2.89 (s, 3H), 2.95(q, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.01-4.15 (m, 3H, 1H ex D₂O),7.12-7.15 (m, 2H), 7.40 (d, 1H), 7.66-7.76 (m, 3H); ¹³C NMR (CDCl₃)δ18.5, 25.5, 26.1, 28.5, 30.1, 40.5, 43.2, 45.7, 55.5, 64.6, 105.8,119.2, 126.1, 126.5, 127.3, 129.1, 129.4, 133.9, 136.1, 157.8, 174.9; MS(ESI) m/z 430.6 (M+Na)⁺ (C₂₁H₂₉NO₅Sna requires 430.6).

The syntheses described in Examples 48 and 49 are outlined in Scheme 18.

EXAMPLE 48

Compound 116 (Scheme 18). To a solution of aminopentanol 113 (3.1 g, 30mmol) and triethylamine (TEA) (4.2 ml, 3.03 g, 30 mmol) in 50 ml ofanhydrous THF was added dropwise p-toluenesulfonyl chloride 115 (5.7 g,30 mmol) in 50 ml of THF at 0° C. The resulting solution was continuedto stir at 0° C. and then rt for 2 h. To the reaction solution was added500 ml of water and the resulted mixture was extracted with EtOAc. Thecombined organic phase was washed with water twice, 0.5 N HCl solutiononce, 5% NaHCO₃ solution once and water once. The organic phase wasdried (Na₂SO₄) and evaporated under high vacuum to give 4.87 g (63%) ofthe compound 116 as a white oil. The compound was used to preparecompound 118 without further purification; ¹H NMR (CDCl₃) δ1.33-1.37 (m,2H), 1.45-1.51 (m, 4H), 2.41 (s, 3H), 2.91 (t, 2H), 3.57 (t, 2H), 7.30(d, 2H), 7.72 (d, 2H); MS (ESI) m/z 280.5 (M+Na)⁺ (C₁₂H₁₉NO₃SNa requires280.4).

Compound 118 (Scheme 18). To a solution of compound 116 (1.29 g, 5mmol), naproxen 1 (1.15 g, 5 mmol) and DMAP (0.12 g, 1 mmol) in CH₂Cl₂was added DCC (1.03 g, 5 mmol) at 0° C. The resulting solution wasstirred at 0° C. for 2h and then at rt for another 2 h. The solid wasfiltered off and the solvent was evaporated. The residue was dissolvedin EtOAc and filtered to remove more solid. The filtrate was washed withwater three times, dried (Na₂SO₄) and concentrated. The product waspurified by flash chromatography on a silica gel column using ethylether as an eluent to give 2.06 g (88%) of the compound 118 as a solid;¹H NMR (CDCl₃) δ1.13-1.18 (m, 2H), 1.25-1.34 (m, 2H), 1.45-1.51 (m, 2H),1.55 (d, 3H), 2.40 (s, 3H), 2.77 (q, 2H), 3.81 (q, 1H), 3.90 (s, 3H),3.96-4.02 (m, 2H), 4.47 (t, 1H, ex D₂O), 7.12-7.14 (m, 2H), 7.26 (d,2H), 7.38 (d, 1H), 7.65-7.70 (m, 5H); MS (ESI) m/z 492.5 (M+Na)⁺(C₂₆H₃NO₅SNa requires 492.6).

EXAMPLE 49

Compound 117 (Scheme 18). Compound 117 was prepared by the similarprocedure as described above for compound 116 from 6-amino-1-hexanol 114(3.5 g, 30 mmol) and compound 115 (5.7 g, 30 mmol). The product waspurified by flash chromatography on a silica gel column using ethylether as an eluent to give 6.5 g (80%) of the compound 117 as a whitesolid; ¹H NMR (CDCl₃) δ1.26-1.29 (m, 4H), 1.43-1.49 (m, 4H), 2.40 (s,3H), 2.89 (t, 2H), 3.57 (t, 2H), 7.27 (d, 2H), 7.73 (d, 2H); MS (ESI)m/z 272.4 (M+H)⁺ (C₁₃H₂₂NO₃S requires 272.4).

Compound 119 (Scheme 18). Compound 119 was prepared by the similarprocedure as described above for compound 118 from compound 117 (1.36 g,5 mmol), naproxen 1 (1.15 g, 5 mmol), DCC (1.03 g, 5 mmol) and DMAP(0.12 g, 1 mmol). The product was purified by flash chromatography on asilica gel column using ethyl ether as an eluent to give 2.04 g (84%) ofthe compound 119 as a white solid; ¹H NMR (CDCl₃) δ1.11 (m, 4H),1.23-1.29 (m, 2H), 1.46-1.56 (m, 2H), 1.56 (d, 3H), 2.40 (s, 3H), 2.79(q, 2H), 3.82 (q, 1H), 3.91 (s, 3H), 3.96-4.05 (m, 2H), 4.43 (t, 1H, exD₂O), 7.11-7.14 (m, 2H), 7.26-7.29 (m, 2H), 7.37-7.39 (q, 1H), 7.64-7.72(m, 5H); ¹³C NMR (CDCl₃) δ18.5 21.7, 25.4, 26.1, 28.4, 29.5, 43.1, 45.7,55.5, 64.6, 105.8, 119.1, 126.1, 126.4, 127.3, 129.1, 129.4, 129.8,133.8, 136.1, 137.2, 143.5, 157.8, 174.1; MS (ESI) m/z 484.7(M+H)⁺(C₂₇H₃₄NO₅S requires 484.6).

The syntheses described in Examples 50 and 51 are outlined in Scheme 19.

EXAMPLE 50

Compound 123 (Scheme 19). A mixture of naproxen sodium 120 (2.52 g, 10mmol) and propanesulton 121 (1.22 g, 10 mmol) in 50 ml ofN,N-dimethylformamide (DMF) was stirred at 50-60° C for 30 min. To thereaction solution was added 150 ml of acetone and then stood still for 1h. Filtration and washing by acetone provided 3.2 g (86%) of thecompound 123 as a white powder; ¹H NMR (D₂O) δ1.37 (d, 3H), 1.93-1.97(m, 2H), 2.74-2.77 (m, 2H), 3.72 (q, 1H), 3.72 (s, 3H), 4.01-4.05 (m,1H), 4.08-4.11 (m, 1H), 6.97-7.00 (m, 2H), 7.20-7.22 (q, 1H), 7.44 (s,1H), 7.50 (t, 2H); ¹³C NMR (D₂O) δ16.7, 23.1, 44.4, 46.9, 54.6, 63.2,105.4, 117.9, 125.1, 125.5, 126.7, 128.1, 128.7, 132.7, 134.9, 156.3,176.4; MS (ESI) m/z 397.1 (M+Na)⁺ (C₁₇H₁₉Na₂O₅S requires 397.4).

EXAMPLE 51

Compound 124 (Scheme 19). Compound 124 was prepared by the similarprocedure as described above for compound 123 from butanesulton 122(1.02 ml, 1.36 g, 10 mmol) and naproxen sodium 120 (2.52 g, 10 mmol).After reaction, acetone was added and the solid was filtered and washedwith acetone to give 1.3 g (34%) of the compound 124 as a white powder;¹H NMR (D₂O) δ1.22 (d, 3H), 1.34-1.38 (m, 2H), 1.50-1.56 (m, 2H), 2.65(t, 2H), 3.44 (s, 3H), 3.47 (m, 1H), 3.74-3.77 (m, 1H), 3.83-3.86 (m,1H), 6.74 (s, 1H), 6.78-6.81 (d, 1H), 7.05 (d, 1H), 7.22-7.29 (m, 3H);MS (ESI) m/z 411.2 (M+Na)⁺ (C₁₈H₂₁Na₂O₆S requires 411.2).

The synthesis described in Example 52 is outlined in Scheme 20.

EXAMPLE 52

Compound 125 (Scheme 20). To a mixture of diclofenac 29 (2.96 g, 10mmol), methylsulfonylethanol 48 (1.24 g, 10 mmol) and DMAP (0.24 g, 2mmol) in 50 ml of CH₂Cl₂ was added DCC (2.06 g, 10 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 2 h. The mixture was filteredand the filtrate was evaporated. The residue was washed with methanol togive 1.83 g (92%) of the compound 125 as a white powder; ¹H NMR (CDCl₃)δ2.75 (s, 3H), 3.30 (t, 2H), 3.84 (s, 2H), 4.58 (t, 2H), 6.51 (d, 1H),6.93 (t, 1H), 7.00 (t, 1H), 7.12 (t, 1H), 7.19 (d, 1H), 7.34 (d, 2H);¹³C NMR (CDCl₃) δ38.5, 42.1 54.0,58.8, 118.3, 122.2, 123.4, 124.7,128.6, 129.1, 129.9, 131.1, 137.6, 142.8, 171.5; MS (ESI) m/z 402.4 M⁺(C₁₇H₁₇Cl₂NO₄S requires 402.4).

The synthesis described in Example 53 is outlined in Scheme 21.

EXAMPLE 53

Compound 127 (Scheme 21). To a mixture of 4-amino-1-butanol 126 (9 g,100 mmol) and K₂CO₃ (34.5 g, 250 mmol, 2.5 equiv) in 200 ml ofacetonitril was added dropwise methanesulfonyl chloride 96 (6.95 ml,10.3 g, 90 mmol, 3 equiv) in 100 ml of CH₃CN at 0° C. The resultingsolution was stirred at 0° C. for 1 h. The reaction mixture was filteredand the solvent was evaporated. The residue was purified by flashchromatography on a silica gel column using 50:1 CH₂Cl₂-MeOH as aneluent to give 3.45 g (21%) of the compound 127 as a white powder; ¹HNMR (CDCl₃) δ1.42-1.49 (m, 4H), 2.89 (s, 3H), 2.91 (q, 2H), 3.39 (q,2H), 4.39 (t, 2H), 6.91 (t, 1H, ex D₂O); ¹³C NMR (CDCl₃) δ26.1, 29.6,42.4, 60.2, one peak is covered by DMSO-d₆ peaks; MS (ESI) m/z 190.1(M+Na)⁺ (C₅H₁₃NO₃SNa requires 190.2).

Compound 128 (Scheme 21). Compound 128 was prepared by the similarprocedure as described above for the compound 125 from diclofenac 29(1.48 g, 5 mmol), compound 127 (0.83 g, 5 mmol), DCC (1.03 g, 5 mmol)and DMAP (0.12 g, 1 mmol). The product was purified by recrystallizationfrom CH₂Cl₂-hexanes to give 1.5 g (67%) of the compound 128 as a whitepowder; ¹H NMR (CDCl₃) δ1.57-1.62 (m, 2H), 1.70-1.74 (m, 2H), 2.91 (s,3H), 3.11 (q, 2H), 3.80 (s, 2H), 4.17 (t, 2H), 4.44 (t, 1H, ex D₂O),6.54 (d, 1H), 6.87 (bs, 1H, ex D₂O), 6.94-7.00 (m, 2H), 7.12 (t, 1H),7.23 (t, 1H), 7.34 (d, 2H); ¹³C NMR (CDCl₃) δ25.8, 26.8, 38.8, 40.5,42.9, 64.7, 118.4, 122.2, 124.3, 124.4, 128.2, 129.1, 129.7, 131.1,137.9, 142.9, 172.5; MS (ESI) m/z 445.3 M⁺ (C₁₉H₂₂Cl₂N₂O₄S requires445.3).

The synthesis described in Example 54 is outlined in Scheme 22.

EXAMPLE 54

Compound 130 (Scheme 22). Compound 130 was prepared by the similarprocedure as described above for the compound 125 from diclofenac 29(1.48 g, 5 mmol), compound 129 (1.22 g, 5 mmol), DCC (1.03 g, 5 mmol)and DMAP (0.12 g, 1 mmol). The product was purified by recrystallizationfrom CH₂Cl₂-hexanes to give 1.3 g (50%) of the compound 130 as a whitepowder; ¹H NMR (CDCl₃) δ1.47-1.51 (m, 2H), 1.62-1.66 (m, 2H), 2.41 (s,3H), 2.90-2.94 (q, 2H), 3.77 (s, 2H), 4.09(t, 2H), 4.34 (t, 1H, ex D₂O),6.53 (d, 1H), 6.86 (bs, 1H, ex D₂O), 6.93-7.00 (m, 2H), 7.11(m, 1H),7.20 (d, 1H), 7.28-7.35 (m, 4H), 7.72 (d, 2H); MS (ESI) m/z 544.2(M+Na)⁺ (C₂₅H₂₆Cl₂N₂O₄SNa requires 544.4).

The synthesis described in Example 55 is outlined in Scheme 23.

EXAMPLE 55

Compound 132 (Scheme 23). To a solution of 4-(hydroxyphenyl)-1-propanol131 (3.04 g, 20 mmol) in 20 ml of pyridine was added compound 115 (15.2g, 80 mmol, 4 equiv) at 0° C. The resulting solution was stirred at 0°C. for 2 h and then at rt for another 2 h. To the reaction solution wasadded 200 ml of water. The resulting mixture was extracted with EtOActwice. The combined organic phase was washed with water five times, 0.5NHCl solution once, 5% Na₂CO₃ solution once and water again. The organicphase was dried (Na₂SO₄) and the solvent was evaporated to give 7.9 g(86%) of the compound 132 as a pale yellow oil; ¹H NMR (CDCl₃) δ1.90 (m,2H), 2.4 (s, 6H), 2.6 (t, 2H), 3.98 (t, 2H), 6.82-6.84 (q, 2H), 6.97 (d,2H), 7.29-7.34 (q, 4H), 7.68 (d, 2H), 7.76 (d, 2H); MS (ESI) m/z 483.3(M+Na)⁺ (C₂₃H₂₄O₄S₂Na requires 483.5).

Compound 134 (Scheme 23). A mixture of diclofenac sodium 133 (1.59 g, 5mmol), compound 132 (2.3 g, 5 mmol) and K₂CO₃ (1.38 g, 10 mmol) wasstirred at rt for 22 h. After reaction, water and EtOAc were added andthe two layers were separated. The organic phase was washed with waterfour times, dried (Na₂SO₄) and concentrated. The residue was purified byflash chromatography on a silica gel column using 5:1 CH₂Cl₂-hexanes asan eluent to give 1.7 g (59%) of the compound 134 as a pale yellow oil;¹H NMR (CDCl₃) δ1.90-1.96 (m, 2H), 2.43 (s, 3H), 2.60 (t, 2H), 3.79 (s,3H), 4.12 (t, 2H), 6.55 (d, 1H), 6.87 (t, 3H), 6.94-7.01 (m, 4H),7.09-7.13 (m, 1H), 7.22-7.35 (m, 5H), 7.69 (d, 2H); ¹³C NMR (CDCl₃)δ22.1, 30.4, 31.8, 32.5, 64.8, 118.7, 122.5, 122.7, 124.5, 124.8, 128.5,128.9, 129.3, 129.9, 129.95, 130.1, 131.2, 132.9, 138.2, 140.5, 143.1,145.7, 148.4, 172.7; MS (ESI) m/z 584.3 M⁺ (C₃₀H₂₇Cl₂NO₅S requires584.5¹).

EXAMPLE 56 Reduced Numbers of Intestinal Ulcers in Rat Acute andSubacute Enteropathy Models by the Invention Modified NSAID (Compound19)! a Prodrug of Naproxen

NSAIDs are important drugs used to treat acute and chronic inflammationas well as pain and fever. The major limitation to NSAID use is theoccurrence of gastrointestinal ulcers and erosions. These side effectsare produced by a combination of local and systemic effects. Attemptshave been made to circumvent the local side effects of NSAIDs by makingthem as prodrugs, which will bypass the stomach, but so far this has notbeen clearly successful. It is demonstrated here that the inventionmodified NSAIDs substantially reduce GI toxicity, while exhibiting doseequivalent efficacy in anti-inflammation activity in both acute andchronic inflammation animal models.

Sprague-Dawley rats (male, 150-200 g), were orally dosed once daily foreither 3 days (acute model) or 14 days (subacute model). Twenty-fourhours after the last dose, the rats were injected i.v. with Evans Blue(5 ml/kg, 10 mg/ml) to stain the ulcers. Ten to twenty minutes later theanimals were sacrificed by CO2 inhalation and the intestines removed,opened lengthwise and the contents removed. The long dimensions of allulcers were measured using a ruler and summed to give a total ulcerscore.

In the acute model (FIG. 1), ulceration after dosing with an inventionmodified NSAID (compound 19) was 15% of that seen with an equimolar doseof naproxen. PEG had no ulcerogenic effect. In the subacute model (FIG.2), ulceration was less than 5% of that seen with a corresponding doseof naproxen at all three doses used. Again, PEG had no effect. Theseresults suggest that invention modified NSAIDs are much less ulcerogenicthan naproxen.

EXAMPLE 57 Reduction of Chronic Hindlimb Inflammation in the RatAdjuvant Arthritis Model by the Invention Modified NSAID (Compound 19),a Prodrug of Naproxen

NSAIDs are useful in the treatment of both chronic and acuteinflammatory conditions. Efficacy in chronic inflammation can beestimated using the rat adjuvant arthritis model. In this model Lewismale rats (175-250 g) are injected intradermally in the footpad with M.tuberculosis powder suspended in mineral oil at 5 mg/ml. Progressiveswelling of the uninjected paw and ankle joint between days 5 and 15 ismeasured by plethysmometry.

Rats were dosed daily by oral gavage with 5 ml/kg of naproxen at 3 to 30mg/kg in phosplate buffered saline (PBS) and with equimolar doses of aninvention modified NSAID at 1 ml/kg in PEG 300. The results (FIG. 3)show that the invention modified NSAID resulted in antiinflammatoryeffects comparable to those of naproxen in this model.

EXAMPLE 58 Reduction of Acute Hindlimb Inflammation in the RatCarrageenan-induced Hindlimb Edema Model by the Invention Modified NSAID(Compound 19), a Prodrug of Naproxen

Efficacy of NSAIDs in acute inflammation can be estimated by usingintraplantar injection of carrageenan in the rat. Sprague-Dawley rats(200-250 g male) are injected intradermally in the footpad with 50 (1 ofa 1% carrageenan solution in PBS. Swelling of the injected paw ismeasured 3 & 4 hours later, using a plethysmometer.

Pretreatment with oral naproxen one hour before the carrageenaninjection at 10 mg/kg resulted in an approximately 50% reduction inswelling at both time points (Table 1). An equimolar dose of aninvention modified NSAID reduced inflammation to the same degree at bothtime points. These results suggest that invention modified NSAIDs arecomparable in effect to naproxen at 10 mg/kg.

TABLE 1 Effects of naproxen and the invention modified NSAID (compound19) on paw volume increase in carrageenan-induced inflammation in rats.Treatment 4 Hours 5 Hours Vehicle 0.73 ± 0.10 0.85 ± 0.10 Naproxen (1mg/kg) 0.63 ± 0.07 0.75 ± 0.08 Naproxen (10 mg/kg) 0.32 ± 0.05* 0.39 ±0.07* Compound 19 (1.75 mg/kg) 0.78 ± 0.04 0.93 ± 0.04 Compound 19 (17.5mg/kg) 0.34 ± 0.06* 0.40 ± 0.06* P < 0.05 vs Vehicle by unpaired t-test.

Invention modified NSAIDs are seen to have antiinflammatory activitysimilar to naproxen in the chronic adjuvant arthritis and acutecarrageenan hindlimb edema rat models. The tendency to cause intestinalulcers is reduced substantially invention modified NSAID. Thus,invention modified NSAIDs provide an effective prodrug form of naproxenwith reduced intestinal side effects.

EXAMPLE 59 Plasma Pharmacokinetics of Naproxen and the InventionModified NSAID After Oral Administration in Rats

The invention compound (compound 19) is a naproxen prodrug, which is aconjugate of naproxen and tosylate. Oral administration of the inventioncompound resulted in the release of free naproxen. The pharmacokineticsof naproxen release from the invention modified NSAID and its parentdrug, naproxen, was evaluated in rats after oral administration.

The carotid artery of Sprague-Dawley rat (250-350 g, male) wascatheterized at least one day before drug administration and flushedwith 30% polyvinyl pyrrolidone (PVP) (400 U/mL of heparin) to maintainpatency. At predetermined time points (see Table 2), blood samples (250(L) were collected by unhooking the flushing syringe and letting theblood flow out of the catheter and into the centrifuge tubes. Aftercentrifugation (13,000 rpm, 10 min, 4° C.), the plasma samples werecollected and analyzed in the same day.

TABLE 2 Rat group assignment and doses Test Article Group # Rat # Dose*(mg/kg) Sample Time Naproxen 1 1, 2, 3, & 4 Oral (2 mg/kg) 5 min, 0.5,1, 4, 7, 10, 13, 16, 19, 22, & 24 hrs Invention 2 5, 6, 7, & 8 Oral (2mg/kg) 15 min, 0.5, 1, 3, Compound 5, 6, 7, 8, 22, 23, 19 & 24 hrs*Indicates amount of naproxen in dose.

Aliquot of plasma sample (100 μL) was mixed with 200 μL of acetonitrile.After vortexing and centrifugation (13,000 rpm, 10 min, 4° C.), 200 (Lof supernatant was removed and added to 300 (L of a 58:42 mixture of 50mM phosphate buffer (pH 5.0) and acetonitrile. Following vortexing andcentrifugation, 25 L of supernatant was removed and analyzed by HPLCwith a UV detection system.

The average plasma concentration at each time point was calculated andutilized in a pharmacokinetic analysis. Noncompartmental pharmacokineticanalysis was carried out using WinNolin (Pharsight, Mountainview,Calif.) to calculate the maximum concentration (C_(max)), time tomaximum concentration (T_(max)), area under the curve from zero to thelast time point (AUC_(last)), the area under the curve from zero toinfinite time (AUC_(inf)), and the terminal phase half life(Beta-t_(½)).

The AUC_(all), AUC_(INF, and t) _(½) of naproxen from naproxen and amodified form of naproxen according to the invention were found to besimilar (Table 3). On the other hand, for the invention modified form ofneproxen, the C_(max) was lower and the T_(max) longer, compared tonaproxen (see Table 3).

TABLE 3 Non-Compartmental Pharmacokinetic Analysis of naproxen and theinvention modified form of naproxen according to the (compound 19) afteroral administration in rats AUC_(all) AUC_(INF) Dose* C_(max) T_(max)(μg*hr/ (μg*hr/ t_(1/2) Drug (mg/kg) (μg/mL) (hrs) mL) mL) (hrs) NNaproxen 2 7.77 ± 0.5 ± 50 ± 6  55 ± 7  6.2 ± 0.4 4 4.13 0.5 Invention 23.87 ± 6.8 ± 49 ± 10 56 ± 14 6.8 ± 2.7 4 modified 1.05 1.5 naproxen*Indicates amount of naproxen in dose.

Following oral naproxen administration, the naproxen plasma levels wereat the highest at the first time-point (5 minutes) then declined in abi-exponential manner. In contrast, after oral administration of amodified form of naproxen according to the invention, the maximumnaproxen levels were observed at a much later time (T_(max) of 6.8±1.5hrs). The similar AUC_(all), AUC_(INF), and T_(½) values but lowerC_(max) and longer T_(max) values supports the conclusions drawn fromthe results obtained from pharmacological studies, i.e. that a modifiedform of naproxen according to the invention conjugate has equivalentpharmacological efficacy and greatly improved gastrointestinal safetyprofile compared to naproxen.

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

What is claimed is:
 1. A method for the alleviation of side effectsinduced by the administration of a non-steroidal anti-inflammatory drug(NSAID) to a subject, said method comprising chemically modifying saidNSAID prior to administration to a subject, wherein said NSAID ischemically modified by covalent attachment thereto of asulfur-containing functional group to give a structure: X-L-Z wherein:X=a non-steroidal anti-inflammatory drug (NSAID), L=a covalent bond, alinker, or a spacer, Z=a sulfur-containing functional group containing asubstituted or unsubstituted hydrocarbyl moiety, wherein thesulfur-containing functional group is sulfoxide, sulfonate, reversesulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfinate, orreverse sulfinate, wherein said chemically modified NSAID a) reduces themaximum concentration (C_(max)) relative to the unmodified NSAID and b)maintains a therapeutically effective concentration of said NSAID inplasma upon administration to said subject.
 2. The method according toclaim 1, wherein the C_(max) is reduced relative to the unmodified NSAIDby about 10% to 90%.
 3. The method according to claim 2, wherein theC_(max) is reduced relative to the unmodified NSAID by about 20% to 80%.4. The method according to claim 3, wherein the C_(max) is reducedrelative to the unmodified NSAID by about 40% to 70%.
 5. The methodaccording to claim 1, wherein the NSAID is chemically modified so as toachieve a C_(max) upon administration at or below the IC₅₀ value for COX1 enzyme.
 6. The method according to claim 1, wherein the NSAID isacetaminophen, aspirin, ibuprofen, choline magnesium salicylate, cholinesalicylate, diclofenac, diflunisal, etodolac, fenprofen calcium,flurobiprofen, indomethacin, ketoprofen, carprofen, indoprofen,ketorolac tromethamine, magnesium salicylate, meclofenamate sodium,mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac,tolmetin, meloxicam, nabumetone, naproxen, lornoxicam, nimesulide,indoprofen, remifenzone, salsalate, tiaprofenic acid, or flosulide. 7.The method according to claim 6 wherein said NSAID is naproxen, aspirin,ibuprofen, flurbiprofen, indomethacin, ketoprofen, carprofen, oretodolac.
 8. The method according to claim 1 wherein the NSAID isadministered to a subject for the treatment of a pathological condition.9. The method according to claim 8 wherein said pathological conditionis inflammation.
 10. The method according to claim 8 wherein the NSAIDis administered to a subject for the treatment of anelgesia.
 11. Amethod for alleviating the systemic toxicity of a non-steroidalanti-inflammatory drug (NSAID), said method comprising chemicallymodifying said NSAID prior to administration to a subject, wherein saidNSAID is chemically modified by covalent attachment thereto of asulfur-containing functional group to give a structure: X-L-Z wherein:X=a non-steroidal anti-inflammatory drug (NSAID), L=a convalent bond, alinker, or a spacer, Z=a sulfur-containing functional group containing asubstituted or unsubstituted hydrocarbyl moiety, wherein thesulfur-containing functional group is sulfoxide, sulfonate, reversesulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfinate, orreverse sulfinate, wherein said chemically modified NSAID a) reduces themaximum concentration (C_(max)) relative to the unmodified NSAID and b)maintains a therapeutically effective concentration of said NSAID inplasma upon administration to said subject.
 12. A method for reducingthe maximum concentration in plasma achieved upon administration of anon-steroidal anti-inflammatory drug (NSAID), said method comprisingmodifying the NSAID by covalent attachment thereto of asulfur-containing functional group containing an optionally substitutedhydrocarbyl moiety.
 13. A method for the controlled release in vivo of anon-steroidal anti-inflammatory drug (NSAID), said method comprisingchemically modifying said NSAID by covalent attachment thereto of asulfur-containing functional group to give a structure: X-L-Z wherein:X=a non-steroidal anti-inflammatory drug (NSAID), L=a convalent bond, alinker, or a spacer, Z=a sulfur-containing functional group containing asubstituted or unsubstituted hydrocarbyl moiety, wherein thesulfur-containing functional group is sulfoxide sulfonate, reversesulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfinate, orreverse sulfinate, wherein said chemically modified NSAID reduces themaximum concentration (C_(max)) achieved in plasma upon administrationto a subject.
 14. A method for the treatment of a subject afflicted witha pathological condition, said method comprising administering to saidsubject a therapeutically effective amount of a chemically modifiednon-steroid anti-inflammatory drug (NSAID), wherein said chemicallymodified NSAID is modified by covalent attachment thereto of asulfur-containing functional group to give a structure: X-L-Z wherein:X=a non-steroidal anti-inflammatory drug (NSAID), L=a convalent bond, alinker, or a spacer, Z=a sulfur-containing functional group containing asubstituted or unsubstituted hydrocarbyl moiety, wherein thesulfur-containing functional group is sulfoxide, sulfonate, reversesulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfinate, orreverse sulfinate, wherein the NSAID is effective for treatment of saidcondition, and wherein the modified NSAID has a reduced C_(max) value.15. The method according to claim 14, wherein said pathologicalcondition is septic shock, hemorrhagic shock, anaphylactic shock, toxicshock syndrome, ischemia, cerebral ischemia, administration ofcytokines, overexpression of cytokines, ulcers, inflammatory boweldisease, diabetes, arthritis, asthma, Alzheimer's disease, Parkinson'sdisease, multiple sclerosis, cirrhosis, allograft rejection,encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis,lymphocytic choriomeningitis, glomerulonephritis, uveitis, ileitis,inflammation, burn, infection, hemodialysis, chronic fatigue syndrome,stroke, cancers, cardiopulmonary bypass, ischemic/reperfusion injury,gastritis, adult respiratory distress syndrome, cachexia, myocarditis,autoimmune disorders, eczema, psoriasis, heart failure, heart disease,atherosclerosis, dermatitis, urticaria, systemic lupus erythematosus,AIDS, AIDS dementia, chronic neurodegenerative disease, pain, priapism,cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia,depression, premenstrual syndrome, anxiety, addiction, headache,migraine, Huntington's disease, epilepsy, neurodegenerative disorders,gastrointestinal motility disorders, obesity, hyperphagia, solid tumors,malaria, hematologic cancers, myelofibrosis, lung injury,graft-versus-host disease, head injury, CNS trauma, hepatitis, renalfailure, liver disease, drug-induced lung injury, myasthenia gravis(MG), ophthalmic diseases, post-angioplasty, restenosis, angina, orcoronary artery disease.
 16. The method according to claim 15, whereinsaid pathological condition is arthritis.
 17. The method according toclaim 16, wherein said arthritis is rheumetoid arthritis orosteoarthritis.
 18. The method according to claim 15, wherein saidpathological condition is headache.
 19. The method according to claim18, wherein said headache is a migraine.
 20. The method according toclaim 15, wherein said pathological condition is pre-menstrual syndrome.21. The method according to claim 15, wherein said pathologicalcondition is pain.
 22. The method according to claim 21, wherein saidpain is chronic pain.
 23. The method according to claim 22, wherein saidpain is post-surgical pain.
 24. In a method for the administration of anon-steroidal anti-inflammatory drug (NSAID) to a subject for thetreatment of a pathological condition, the improvement comprisingmodifying the NSAID so as to reduce the C_(max) value achieved uponadministration to a subject, wherein said NSAID is modified by covalentattachment thereto of a sulfur-containing functional group to give astructure: X-L-Z wherein: X=a non-steroidal anti-inflammatory drug(NSAID), L=a covalent bond, a linker, or a spacer, Z=a sulfur-containingfunctional group containing a substituted or unsubstituted hydrocarbylmoiety, wherein the sulfur-containing functional group is sulfoxide,sulfonate, reverse sulfonate, sulfonamide, reverse sulfonamide, sulfone,sulfinate, or reverse sulfinate.
 25. A method for the preparation of amodified non-steroidal anti-inflammatory drug (NSAID) having reducedpropensity to induce side effects, said method comprising modifying theNSAID so as to reduce the C_(max) value achieved upon administration toa subject, wherein said NSAID is modified by covalent attachment theretoof a sulfur-containing functional group to give a structure: X-L-Zwherein: X=a non-steroidal anti-inflammatory drug (NSAID), L=a covalentbond, a linker, or a spacer, Z=a sulfur-containing functional groupcontaining a substituted or unsubstituted hydrocarbyl moiety, whereinthe sulfur-containing functional group is sulfoxide, sulfonate, reversesulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfinate, orreverse sulfinate.